Ethers of alpha-phenyl-2-aminocycloalkanemethanols



United States Patent 3,499,033 ETHERS OF a-PHENYL-Z-AMINOCYCLO- ALKANEMETHANOLS Jacob Szmuszkovicz Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware t No Drawing. Filed Jan. 6, 1967, Ser. No. 607,627

Int. Cl. C07c 91/00, 87/32, 103/10 US. Cl. 260570.5 9 Claims ABSTRACT OF THE DISCLOSURE a-Phenyl-Z-aminocycloalkanemethanols, ethers, esters thereof and acid addition salts, N-oxides and quaternary ammonium salts thereof, which can be additionally substituted in the phenyl group with lower alkyl, lower alkoxy, halogen and --CF;, and in the amino group with alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenyl, substituted phenyl, benzyl and acyl are prepared by reacting (1) a 2-oxocycloalkyl phenyl ketone with a primary or secondary amine in the presence of a benzeuesulfonic acid, (2) hydrogenating the products of (1) in the presence of noble metal catalyst; and if desired, esterifying or etherifying the product of step (2). The novel compounds are stimulants for the central nervous system of mammals and birds, and intermediates, e.g., for diuretics.

CROSS-REFERENCE TO RELATED APPLICATION This application is related to the application S.N. 556,- 892, filed June 13, 1966.

BACKGROUND OF THE INVENTION Field of the invention This invention relates to new organic compounds and is particularly concerned with new central nervous system stimulating 1,3-amino alcohols, the intermediates thereof, the ethers, esters, N-oxides, acid addition salts and quaternary ammonium salts thereof as well as the process for production therefor.

SUMMARY OF THE INVENTION The novel compounds and the process of invention can be illustratively represented by the following sequence of formulae:

wherein n has the value of 1 to 4, inclusive; wherein R 3,499,033 Patented Mar. 3, 1970 ice R4 is selected from the group consisting of the combinations H alk d v alk an 9.12

wherein each alk is an alkyl of from 1 to 6 carbon atoms, inclusive,

H benzyl benzyl alk wherein alk is an alkyl radical having from 1 to 6 carbon atoms, inclusive,

hydroxyalkyl in which hydroxyalkyl is defined as above,

alkoxyalkyl in which alkoxyalkyl is defined as above,

cycloalkyl in which cycloalkyl is defined as above, and

phenyl in which phenyl is unsubstituted or substituted; wherein R, R and R are selected from the group of substituents consisting of hydrogen, halogen, alkyl and alkoxy containing from 1 to 6 carbon atoms, inclusive, and CF and wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 2 to 12 carbon atoms, inclusive.

The invention further includes the compounds of Formulae III, IV, Na and IV b when in the form of the N-oxides, acid addition salts and quaternary alkyl ammonium halide salts in which the alkyl group has from 1 to 12 carbon atoms, inclusive, and the halogen can be chlorine, bromine and iodine.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Examples of the cycloalkyl radical, illustratively represented by the formula:

cycloalkyl Illustrative examples of alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, 2-methylbutyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl and the like. Alkyl groups for the quaternary alkyl ammonium halide salts include, in addition to the preceding alkyl groups, others such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The halogen moiety in such salts includes iodine, bromine and chlorine.

Illustrative examples of the acyl groups Ac of hydrocarbon carboxylic acids are particularly the acyl groups of alkanoic acids of 2 to 12 carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, octanoyl, decanoyl, undecanoyl, dodecanoyl; of cycloalkanoic acids, e.g., cyclohexane-carbonyl, B-cyclopentylpropionyl; of benzoic and aralkanoic acids, e.g., benzoy-l, phenylacetyl, 3-phenylpropionyl, mand ptoluoyl, p-ethylbenzoyl, p-propylbenzoyl; of alkenoic acids, e.g., acryloyl, crotonyl, chrysanthenummonocarbonyl, cinnamoyl, hexenoyl; of alkynoic acids, e.g., propioloyl, 2- and 3-butynoyl and the like.

Under halogen substituents for R, R", or R'" is understood fluorine, chlorine, bromine and iodine.

Representative hydroxyalkyl groups are 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl, 6- hydroxyhexyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxypentyl and the like.

Representative alkoxyalkyl groups comprise such radicals as methoxymethyl, Z-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, S-methoxypentyl, 3-methoxypentyl, 2,2- diethoxyethyl, and the like.

Substituted phenyl signifies the radical of formula:

wherein R is selected from the group consisting of halogen, alkyl and alkoxy containing from 1 to 6 carbon atoms, inclusive, and -CF for example, o-, m-, and pch-lorophenyl, o-, m-, and p-fluorophenyl, o-, m-, and ptolyl, o-, m-, and p-butylphenyl, o-, m-, and p-anisyl, 0-, m-, and p-butoxyphenyl, o-, m-, and p-ethylphenyl, 0-, m-, and p-bromophenyl, o-, mand p-trifluoro-methylphenyl, and the like.

It should be noted that the substituents R and R by definition include the substituents R and R The process of the present invention comprises: heating a diketo compound of Formula I in which one of the radicals on the central carbonyl group is a 2-oxocycloalkyl grouphaving from 5 to 8 carbon atoms, inclusive, and the other group is substituted or unsubstituted phenyl, with an amine of formula:

wherein in R and R are defined as above, in the presence of an acidic catalyst, e.g., benzenesulfonic acid, pchlorobenzene-sulfonic acid, p-toluenesulfonic acid, to give the unsaturated keto compound of Formula II; hydrogenating the thus-obtained compound II in the presence of a hydrogenation catalyst, preferably a noble meta-1 catalyst such as platinum oxide, rhodium, palladium or the like to add at least two molar equivalents of hydrogen, thus yielding the corresponding compound Ill. Those compounds of Formula II in which R or R is benzyl can be submitted to hydrogenation-either simultaneously or consecutively-4o split off the benzyl group and thus to give primary or secondary amines, which can be alkylated, or acylated to give the range of compounds represented by Formula IV. The thus-obtained 1,3-amino alcohols III or IV can be converted to alcohol derivatives such as ethers (Iva) with an alkyl halide (l to 6 carbon atoms) in the presence of a base, or with a lower alkanol (1 to 6 arbon a om n h p esen e of anhydrous, hy-

drogen chloride, and to esters (IVb) with an acid anhydride or acid halide in a suitable organic solvent.

The Formula III compounds, and the amino compounds of Formulae IV, IVa and TV]; can be transformed by neutralization with inorganic and organic acids, into acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, perchlorate, pamoate, cyclohexanesulfamate, methane-sulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, t artrate, citrate, lactate, and the like. By treatment of the tertiary amino compounds of Formula III, IV, IVa and IV!) with peracids such as m-chloroperbenzoic acid, performic acid, peracetic acid, perpropionic acid, perbcnzoic acid, perphthalic acid, and the like, the corresponding N- oxide deravitives are obtained. By treatment of the tertiary amino compounds of Formulae III, N, Na and Nb with alkyl halides, the corresponding quaternary alkyl ammonium halide salts are obtained.

The compounds of Formula IVa including N-oxides, quaternary alkyl ammonium halide salts and acid addition salts thereof are useful stimulating agents, which act on the central nervous system. They can be used for stimulation of the respiratory, medullary, vagal and vasomotoric centers of mammals and birds.

They may be administered to mammals and birds by both oral and parenteral routes in order to produce their pharmacological, i.e., stimulating efiects. For oral administration, the new compounds of Formula IVa as well as the acid addition salts, the N-oxides and the quaternary alkyl ammonium halide salts, can be compounded into solid and liquid unit dosage forms such as tablets, capsules, powders, granules, syrups, elixers and the like, containing the appropriate amounts for treatment. For tablets, common pharmaceutically acceptable carriers are used such as starch, lactose, kaolin, dicalcium phosphate and the like. The compound IVa can also be given as powders, particularly in gelatin capsules with or without carriers such as methylcellulose, magnesium stearate, calcium stearate, talc and the like. For fluid preparations, these compounds may be dissolved or suspended in aqueous alcoholic vehicles with or without buffering agents and flavoring mixtures.

The thus-obtained pharmaceutical formulations are administered to animals for the treatment of conditions associated with respiratory diificulties, e.g., pneumonia, bronchitis, asthma or with heart insulficiencies. In particular these compounds are useful as geriatric stimulants for pet animals. Dosages between 0.110 mg./kg. of body weight per day produce significant stimulation.

The compounds of Formulae IV, IVa and IVb, which are primary amines (R and R are hydrogen) are also useful as intermediates for the production of highly active diuretic compounds, namely, when reacted with 1,5- dibromoor -diiodopentane, these Z-amino-cycloalkane compounds become 2-piperidinocycloalkane compounds. Illustratively, the ether ClS-B-l-[2-(OL,p-dlmthOXYbBl1Zyl)- cyclohexyhpiperidine of melting point 82 to 84 C. [obtained from cis-B-Z-(a,p-dimethoxybenzyl)cyclohexylamine, Example 103], produced at 5 mg. dosage level per kg. of body Weight of rats a 73% increase in diuresis, as determined by the procedure of Lipschitz et al., I. Pharmacol-Exp. Therap. 79, 97, 1943,

As noted above, the new compounds of Formula HI, and the amino compounds of Formulae IV, IVa and IVb can be used in the form of their acid addition salts with inorganic or organic acids, for example, hydrochlorides, lactates, sulfates, tartrates, hydroiodides, hydrobromides and the like. Morover, the fluosilicates of these compounds are useful mothproofing agents according to U.S. Patents 1,915,334 and 2,075,359. The thiocyanic acid addition salts of the same compounds can be condensed With formaldehyde to form resinous polymers which according to U.'S. Patents 2,425,320 and 2,606,155 are useful pickling inhibitors. The trichloroacetic acid addition salts of the same compounds are useful as herbicides, for examples,

against Johnson grass, yellow foxtail, green foxtail, Bermuda grass and quack grass.

The quaternary alkyl ammonium halides of the tertiary amino compounds of Formulae III, IV, IVa and IVb possess high wetting power and electroconductivity and are thus suitable to prepare electrocardiographic jellies.

A suitable composition of an electrocardiographic jelly thus prepared comprises:

Parts Glycerol Starch Quaternary ammonium salt 60 Water 100 The jelly is prepared by mixing the starch, glycerol and water and then adding the quaternary ammonium salt. The mixture is then allowed to stand for at least two days with occasional agitation to allow the formation of a gel.

The starting materials of Formula I are known in part from the art, e.g., Campbell et al., I. Am. Chem. Soc. 82, 2389 (1960); Linn et al., I. Am. Chem. Soc. 78, 6066 (1956); Eistert et al., Ann. 650, 133 (1961). An elegant method by which the 1,3-diones of the type of Formula I are synthesized consists of the reduction of a selected cycloalkanone with pyrrolidine or piperidine to give the corresponding enamine and to react the enamine with a selected substituted or unsubstituted benzoyl chloride [Campbell et al., I. ()rg. Chem. 28, 379 (1963)]. This particular method is shown repeatedly in the preparations in order to synthesize hitherto unknown 1,3-diones of the type of Formula I.

In carrying out the process of the present invention, a 1,3-diketo compound (I) is reacted with an amine (V) in the presence of an acid catalyst and preferably under conditions in which the water produced in the condensation process is separated from the reaction mixture such as by employing an azeotropic separator together with the reflux condenser. As solvent, essentially water-free organic solvents are used such as benzene, toluene, xylene or the like. The amines used include particularly N- methylbenzylamine, N-ethylbenzylamine, N-propylbenzyl amine, N-butylbenzylamine, ethylamine, isopropylamine, butylamine, pentylamine, hexylamine, dimethylamine, (iiethylamine, dipropylamine, N-methylpentylamine, dibutylamine, dihexylamine, benzylamine, aniline, o-, m-, and ptoluidine, p-butylaniline, 0-, m-, and p-anisidine, o-, m-, and p-chloroaniline, o-, m-, and p-trifluoromethylaniline, Z-hydroxyethylamine, 3-hydroxypropylamine, 2-hydroxypropylamine, 3 hydroxypentylamine, 4 hydroxybutylamine, 6-hydroxyhexylamine, Z-hydroxylamine, 2-ethoxyethylamine, 4-ethoxybutylamine, S-methoxypentylamine, 3 propoxypropylamine, cyclopentylamine, cyclohe'xylamine, cyclooctylamine, and the like.

The reaction is generally carried out at temperatures between 30-150 C. but lower or higher temperatures are operative. Preferably, the reaction is carried out at the reflux temperature of the reaction mixture. The time for completion of the reaction is between 1 hour and 48 hours, but if low temperatures are used, longer reaction times are necessary. When the reaction is terminated, the product is isolated in conventional manner such as evaporating the reaction mixture.

The keto product of Formula II is then hydrogenated in the presence of a catalyst, e.g., platinum oxide, rhod-.

ium and the like, palladium on a carrier, e.g., alumina or charcoal, at a hydrogen pressure between 40 and 60 pounds per square inch. Larger or smaller pressures can be used, but pessures between 5-60 pounds at the beginning of the reaction are found to be most convenient. The reaction can be followed by the hydrogen absorption and can be allowed to go to completion, that is, to the point of addition of 2 molar equivalents of hydrogen to give the alcohol of FormulaIII. After the hydrogenation is completed, the product is isolated by filtering the mixture to remove the catalyst and evaporating the solvent to obtain the alcohol of formula III. The thus-isolated product is purified by conventional means such as by crystallization and recrystallization, chromatography or the like.

Those compounds of Formula II which have one N- benzyl group (R or R is benzyl) can be simultaneously hydrogenated and hydrogenolysed or can be hydrogenolysed after hydrogenation to give those compounds of Formula IV which have at least one hydrogen on the nitrogen atom. If the compound of Formula II has merely R =H and R =benzyl, hydrogenation and hydrogenolysis produces the free primary amino alcohol IV This amino alcohol can be selectively acylated on the amino group or if desired simultaneously on the amino and alcohol groups to give respectively, other alcohols or esters corresponding to Formulae IV and IVb.

The conversion of the alcohol of Formula IV to an ether of Formula IVa is usually achieved by two methods: 1) reacting the alcohol of Formula IV in liquid ammonia containing sodium amide or potassium amide at low temperature with the selected alkyl halide, or (2) re acting the alcohol of Formula IV with a lower alkanol in the presence of hydrogen chloride. The starting tempera ture of the first method is usually the temperature of a Dry Ice-acetone bath, that is, approximately 70 C. and is completed at about room temperature. In the preferred embodiment of this invention, the selected alcohol (IV), is dissolved in ether and is added to liquid ammonia containing sodium amide, under continuous stirring. When this mixture reaches the Dry Ice-acetone bath temperature, a solution of the alkyl halide, preferably an alkyl iodide, is added over a few minutes time to allow cooling. When the calculated amount of alkyl halide is consumed, the reaction mixture in the flask is removed from the Dry Ice-acetone bath and allowed to warm to room temperature under continuous stirring. Instead of sodium amide, other strong basic compounds can be used such as potassium amide, lithium amide and the like. Instead of liquid ammonia and alkali metal amides, other reaction systems can be used, e.g., butyl lithium in the presence of tetrahydrofuran at a temperature range of about 70 to 25 C. After the reaction is terminated, the ether thus produced (IVa) is isolated by conventional procedures such as extraction, evaporation of solvents, formation of amine addition salts such as the hydrochloride, and using the differential water solubility of the hydrochloride and the like. For purification, recrystallization and chromatography are usually employed.

In the second method, the alcohol IV is stirred with a solution of hydrogen chloride gas in a lower alkanol, e.g., methanol, ethanol, propanol, l-butanol, 2-butanol and the like, usually at room temperature. Lower or higher temperatures are operative, however. The product is obtained as a hydrochloride of the amino ether. The free base is obtained by treating the hydrochloride with a base, e.g., 20% aqueous sodium hydroxide, extracting the free base with a water-immiscible solvent, e.g., ether, methylene chloride, chloroform and the like and evaporating the solvent.

Esters (lVb) of the alcohol of Formula IV are usually obtained in conventional manner, that is, treatment of the alcohol with an acid anhydride or acid halide, preferably in solution at room temperature. The solvents used in this reaction are methylene chloride, tetrahydrofuran, pyridine, and the like. The anhydrides used in this reaction are usually of hydrocarbon carboxylic acids, e.g., of alkanoic acids, such as acetic, propionic, butyric, isobutyric, valeric, hexanoic, heptanoic, octanoic acids and the like; of benzoic and aralkanoic acids such as benzoic acid, salicyclic acid, toluic acid, phenylacetic acid, 3-pheny1- propionic acid and the like; of cycloalkanoic acids, e.g., of cyclohexanecarboxylic acid, ocand fl-cyclopentylpropionic acid and the like. The acid halides used in this reaction can be of alkanoic acids, particularly higher alkanoic acids having from 6 to 12 carbon atoms, such as hexanoyl chloride, heptanoyl chloride, octanoyl chloride, decanoyl chloride, undecanoyl chloride, lauroyl chloride or the acid bromides thereof, but the chlorides and bromides of lower alkanoic acids are also useful. The invention also encompasses the use of the anhydrides and acid chlorides and bromides of unsaturated acids such as cinnamic acid, acrylic acid, crotonic acid, propiolic acid, 2-butynoic acid, chrysanthenummonocarboxylic acid and the like. After termination of the reaction, the product is isolated by conventional procedures such as extraction, chromatography, crystallization and the like. Obviously, if a primary or secondary amino group exists in the alcohol IV, the corresponding amides can be simultaneously produced.

Acid addition salts of the amino alcohols (III) and (IV), amino ethers (IVa) and amino esters (IVb) are synthesized in the usual manner, that is, by directly reacting the acid with the free amine, preferably in an aqueous or anhydrous solvent such as water, ether, methanol, ethanol, ethyl acetate or the like. Evaporation of the solvent provides the desired acid addition salt.

N-oxides of the tertiary amino compounds of Formulae III, IV, IVa and IVb are obtained by reacting the compound at a temperature between -30 C., preferably, at the start of the reaction at a temperature between 0-10 C., with a peracid such as performic, peracetic, perpropionigperbenzoic, perphthalic, m-chloroperbenzoic or other organic peracids in a solvent such as methanol, ethanol, ether or the like. Evaporation of the solvent provides the desired N-oxide of the products of Formulae III, IV, IVa and IVb.

The quaternary alkyl ammonium halides of tertiary amino compounds of Formulae III, IV, IVa and IVb are produced by conventional methods such as heating to reflux a solution of the selected compound III, IV, IVa or IVb in the presence of methanol, ethanol, acetonitrile or the like with a selected alkyl halide such as an iodide or bromide or, less desirably, a chloride of methyl, ethyl, propyl, butyl, isobutyl, isopropyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, or isomers of these alkyl compounds. After the reaction is terminated, the reaction mixture is evaporated to dryness to give the product which can be purified by recrystallization from organic solvents such as methanol, ethanol, ether, Skellysolve B hexanes, mixtures thereof and the like.

It is obvious from the configuration of products III, IV, IVa and IVb that these products can exist in more than one isomeric structure since the compounds have at least three asymmetric centers. The present method of producing these compounds favors the production of cis compounds.

The following examples are illustrative of the process and the products of the present invention, but are not to be construed as limiting:

PREPARATION 1 2- 3,4,5 -zrimeth0xy benzoy l cycloh exalzone A mixture of 147 g. (1.5 moles) of cyclohexanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2250 ml. of benzene in a flask equipped with an azeotropic separator. After the water formed during the reaction was collected, the solution was evaporated to dryness in vacuo and the resulting crude oil, consisting of l-pyrrolidino-l-cyclohexene, was used directly for the next step.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in 240 ml. of chloroform was added during a period of 2 hours to a solution of the crude l-pyrrolidin0-1-cyclohexene in 630 ml. of chloroform, under a ni trogen atmosphere, with continuous stirring, While keeping the temperature between 5 to C. After the solution was stirred overnight (about 18 hours) at room temperature (about 22 to 25 C.), there was added 900 ml. of 10% aqueous hydrochloric acid, and the resulting mixture was stirred at room temperature for 2 hours. The aqueous layer was extracted with two 150-ml. portions of chloroform, and the chloroform extracts were combined with the chloroform layer above. The combined extracts were washed with water, saturated aqueous sodium bicarbonate solution, water and saturated salt solution. The thus-obtained chloroform solution was dried by passing it through anhydrous sodium sulfate and the dry solution was evaporated to give a residue which was crystallized from methanol to yield 100 g. of long, colorless needles of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone of melting point l4l142 C.

Arzalysis.-Calcd. for C H O C, 65.74; H, 6.90. Found: C, 65.48; H, 6.84.

PREPARATION 2 2- 3,4,5 -trimeth0xy benzoy l cyclopentanone A mixture of 126 g. (1.5 moles) of cyclopentanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2250 ml. of benzene in a flask equipped with an azeotropic separator. After the calculated amount of Water, produced during the condensation, had been collected, the reaction mixture was evaporated to give as an oil l-pyrrolidino-1-cyclopentene.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in chloroform was added to a chloroform solution of the oily l-pyrrolidino-l-cyclopentene over a period of 1 hour. The reaction mixture was thereupon worked up as in Preparation 1 to give a brown oil weighing 190 g. This oil was dissolved in 500 ml. of ethanol and the ethanol solution was added to a solution of 172 g. of cupric acetate monohydrate in 2600 ml. of water. The mixture was stirred for hour, cooled and filtered, providing a crude copper complex of 2-(3,4,5-trimethoxybenzoyl)cyclopentanone. This product was crystallized from methylene chloride to give 70 g. of the pure copper complex melting at 206-208 C.

AnaZysis.-Calcd. for C H CuO C, 58.29; H, 5.54; Cu, 10.28. Found: C, 58.58; H, 5.81; Cu, 9.49.

The thus obtained copper complex (70 g.) was dissolved in 350 ml. of chloroform and decomposed with 670 ml. of 10% aqueous hydrochloric acid to give 60 g. (yield 36%) of 2-(3,4,5-trimethoxybenzoyl)cyclopentanone having a melting point of 8186 C. A sample of this material was recrystallized from Skellysolve B hexanes to give 2-(3,4,5-trimethoxybenzoyl)cyclopentanone of melting point 92-95 C.

Analysis.-Calcd. for C H O C, 64.73; H, 6.52. Found: C, 64.95; H, 6.52.

In a run twice the size of the above synthesis, a yield of 47% was obtained.

PREPARATION 3 2- 3,4,5 -trimethoxybenzoyl cyclohe ptanona A mixture of 500 g. of cycloheptanone (4.5 moles), 785 g. of morpholine (9 moles), 900 ml. of toluene and 5 g. of p-toluenesulfonic acid was refluxed for 23 hours, collecting the water produced in the reaction with an azeotropic separator. Ninety-eight ml. of a lower phase Was collected and discarded. The remaining mixture was then evaporated in vacuo to give an oil which was distilled. The fraction boiling between 119125 C. consisted essentially of 262.7 g. of l-morpholino-I-cycloheptene (32% yield).

In the manner given in Preparation 1, 3,4,5-trimethoxybenzoyl chloride (92.5 g.; 0.4 mole) was reacted with 181.37 g. (1 mole) of l-morpholino-l-cycloheptene. The crude product was crystallized from 500 ml. of methanol and gave a first crop of 26 g. of 2-(3,4,5-trimethoxybenzoyl)cycloheptanone of melting point 99-l00 C. After two more recrystallizations from methanol, the product had a melting point of 107-108 C.

Analysis.Calcd. for C H O C, 66.65; H, 7.24. Found: C, 66.16; H, 7.48.

From the above methanolic filtrate another 48.3 g. of 2-(3,4,5-trimethoxybenzoyl)cycloheptanone was obtained as a second crop. The total yield was 61%.

9 PREPARATION 4 Z- (p-metlzoxy benzoyl cyclohexanone was separated and the aqueous layer extracted twice with 250-ml. portions of chloroform. The original organic layer and the chloroform extracts were combined, washed with water, saturated salt solution, and then dried by passage through anhydrous sodium sulfate and evaporated. The residue resulting from the above evaporation was a brown oil which was dissolved in 1 l. of ethanol and added to a solution of 344 g. of cupric acetate monohydrate in 5200 ml. of water, preheated to 65 C. The mixture was stirred for 0.5 hour, cooled to room temperature and filtered. The obtained precipitate was washed with water and then with ether. It was then dissolved in 800 ml. of chloroform and added to a solution of 300 ml. of concentrated hydrochloric acid in 1100 ml. of water. The mixture was stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted once with chloroform. The combined chloroform original layer and extract were washed with water, saturated salt solution, dried by passing through anhydrous sodium sulfate and evaporated to give a solid which was crystallized from 7 l. of methanol, yielding 136.5 g. of Z-(p-methoxybenzoyl)cyclohexanone having a melting point of 115- 128 C. A second crop of 26 g., melting point l16127 C., was obtained from the mother liquor; the total yield was 71%. A recrystallized sample from methanol of 2- (p-methoxybenzoyl)cyclohexanone had a melting point of 117-122 C.

Analysis.-Calcd. for C I-1 C, 72.39; H, 6.94. Found: C, 72.30; H, 7.05.

PREPARATION 5 2-(p methoxybenzoyl) cyclopentanone In the manner given in Preparation 2, 204 g. (1.2 moles) of p-anisoyl chloride was reacted with l-pyrrolidino-l-cyclopentene prepared from 252 g. (3 moles) of cyclopentanone. The crude product was converted to the copper complex as in Preparation 4, the complex being crystallized from chloroform-ether to give 80 g. of copper complex of 2-(p-methoxybenzoyl)cyclopentanone with a melting point of 252 C. (dec.). The copper complex was decomposed with hydrochloric acid to give 67 g. of an oil which was crystallized from methanol to give 13.9 g. of Z-(p-methoxybenzoyl)cyclopentanone of melting point 82-83 C. The filtrate from the first crystallization was evaporated to dryness and the residue crystallized from ether-Skellysolve B hexanes to give 30.1 g. of a second crop of 2-(p-methoxybenzoyl)cyclopentanone of melting point 7677 C. (total yield 17% Two recrystallizations from methanol gave 2-(p-methoxybenzoyl)cyclopentanone having a melting point of 8387 C.

Analysis.-Calcd. for C H O C, 71.54; H, 6.47. Found: C, 71.83; H, 6.48.

PREPARATION 6 2- (p-ethoxybenzoyl cyclohexzmone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(p-ethoxybenzoyl)cyclohexanone.

1 0 PREPARATION 7 2-(0-meth0xybenz0yl)cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with o-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(o-methoxybenzoyl)cyclohexanone of melting point 65-68 C.

PREPARATION 8 2- (2-meth0xy-4-methylbenzoyl)cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2- methoxy-4-methy1benzoyl)cyclohexanone.

PREPARATION 9 2-(3,5-dimethyl-4-meth0xybenz0yl)cycl0hexan0ne PREPARATION 10 2-(p-lrifluoromethylbenzoyl) cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with p-trifluoromethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(ptrifluoromethylbenzoyl) cyclohexanone.

PREPARATION 1 1 2- (p-chlorobenzoyl) cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with p-chlorobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(p-chlorobenzoyl)cyclohexanone.

PREPARATION 12 2-(o-methylbenzoyl)cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with o-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(o-methylbenzoyl)cyclohexanone.

PREPARATION 13 2- (p-metlzylbenzoyl)Icyclohexanone In the manner given in Preparation 2, l-pyrrolidino-lcyclohexene was reacted with p-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2- (p-methylbenzoyl)cyclohexanone of melting point 108-1l0 C PREPARATION 14 2- (2,4-dimethylbenz0yl cycloheatanone In the manner given in Preparation 2, l-pyrrolidino-L cyclohexene was reacted with 2,4-dimethylbenzoyl chloride in chloroform solution to give, after the copper complex purification (Preparation 2) 2-(2,4-dimethylbenzoyl) cyclohexanone of melting point 5152.5 C

PREPARATION 15 2- (2-meth0xy-4-methylbenzoyl) cyclahexanone In the manner given in Preparation 2, 1-piperidino-1- cyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2- methoxy-4-methylbenzoyl)cyclohexanone.

1 1 PREPARATION 16 Z-(p-ethoxybenzoyl) cyclooctanone In the manner given in Preparation 2, l-morpholinol-cyclooctene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(p-ethoxybenzoyl)cyclooctanone.

PREPARATION l7 2-(2,3,4-Trimeth0xybcnzoyl) cyclooctanone In the manner given in Preparation 2, l-piperidino-lcyclooctene was reacted with 2,3,4-trimethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2,3,4- trimethoxybenzoyl)cyclooctanone.

PREPARATION 18 2- (p-bromobenzoyl cyclooctanone In the manner given in Preparation 2, l-piperidino-lcyclooctene was reacted with p-bromobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(p-bromobenzoyl) cyclooctanone.

PREPARATION 19 2- (m-methylbenzoyl cycloo'ctanone In the manner given in Preparation 2, l-piperidino-lcyclooctene was reacted with rn-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(m-methylbenzoyl)cyclooctanone.

In the same manner given in the foregoing preparations, other 2-benzoylcycloalkanones of Formula 1 (starting compounds) are prepared by reacting a l-cyclicaminol-cycloalkene, wherein the cycloalkene moiety has from to 8 nuclear carbon atoms, inclusive, and the cyclicamino moiety has from 5 to 10 nuclear atoms, inclusive, e.g. morpholino, pyrrolidino, piperidino, and the like with a selected benzoyl chloride. Representative starting materials, thus prepared, include:

and the like.

EXAMPLE 1 CisA-a-(p-methoxyphenyl)-2 (methylamin0) cyclohexanemethanol A solution of 58 g. (0.25 mole) of Z-(p-methoxybenzoyl)cyclohexanone, 91 g. (0.75 mole) of N-methylbenzylamine and 1.6 g. of p-toluenesulfonic acid monohydrate in 2 l. of toluene was heated at reflux for 20 hours, collecting 4 ml. of water in a Dean-Stark trap. The mixture was then concentrated in vacuo to give a residue which was taken up in 400 ml. of ethanol and hydrogenated in the presence of 2.5 g. of platinum oxide catalyst during a period of 18 hours at a hydrogen pressure between 5 and 30 psi. Thereafter, the reaction mixture was filtered to remove the catalyst and the yellowish filtrate was hydrogenated in the presence of 4.0 g. of 10% palladium-on-carbon catalyst for a period of 20 hours. The mixture was again filtered to remove the catalyst and evaporated in vacuo to give a residue. This residue was dissolved in 600 ml. of ether and 500 ml. of 10% aqueous acetic acid. The mixture was stirred for 1 hour, the acetic acid layer was separated, basified with 20% aqueous sodium hydroxide solution and the oil which separated was extracted into methylene chloride. The methylene chloride layer was washed with water, saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. This residue was recrystallized from a mixture of ether-pentane to give a combined amount (from two crops) of material of 31.85 g. (51%) of cis-A-a-(p-methoxyphenyl) 2 (methylamino)cyclohexanemethanol. After recrystallization from Skellysolve B hexanes, the material had a melting point of 88-90 C.

Ultraviolet: k 225 (11,250); 276 (1,550); 282 (1,350).

Analysis.Calcd. for C H NO C, 72.25; H, 9.30; N, 5.62. Found: C, 72.17; H, 9.45; N, 5.55.

EXAMPLE 2 Cis-B-a- (p-methoayphenyD-Z-(methylamino) tcyclohexanemethanol To ml. of trifluoroacetic acid at 0-10 C. was added 10 g. of cis-A-ot-(p-methoxyphenyl)-2-(methylamino) cyclohexanemethanol and the resulting mixture was stirred at 1025 C. for a period of 45 minutes. The reaction mixture was cooled in an ice bath and to it was added 60 g. of ice, 200 ml. of Water, and 200 ml. of 20% aqueous sodium hydroxide. The mixture was stirred for 45 minutes and then extracted with methylene chloride. The methylene chloride extracts were washed with Water, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried material was evaporated to give 9.45 g. of a gummy residue. Vaporphase chromatography showed four components in the gum of which 77.3% was desired B isomer, 14.2% was isomer A and 8.5% was extraneous matter. The gum was dissolved in ml. of pentane and seeded with a sample of the desired product from a previous run [the seed was obtained by converting a sample of gum from a previous run to the oxalate salt of cis-B-ot-(p-methoxyphenyl) 2 (methylamino)cyclohexanemethanol, which after recrystallization from methanol-ether had a melting point of 227-228 C., and then converting the salt to the free base by the addition of aqueous sodium hydroxide] After seeding, crude ClS-B-Ot- (p-methoxyphenyl)- 2-(methylamino)cyclohexanemethanol was obtained in two crops in a total of 7.16 g. (71.6%). The analytical sample, recrystallized from ether-Skellysolve B hexanes, melted at 9293 C.

Ultraviolet: a 225 (11,200); 275 (1,550); 282 (1,300).

Analysis.-Calcd. for C H NO C, 72.25; H, 9.30; N, 5.62. Found: C, 72.61; H, 9.45; N, 5.89.

EXAMPLE 3 Cis-A -u- (p-methoxyp henyl -2- benzylamino) cyclohexanem'ethanol and its hydrochloride A solution of 23.0 g. (0.099 mole) of 2-(p-methoxybenzoyl)-cyclohexanone and 11.0 g. (0.103 mole) of benzylamine in ml. of benzene was heated at reflux for 1.5 hours. The water from the reaction was collected2.2 ml. The reaction mixture was then concentrated in vacuo to give a residue which was taken up in 150 ml. of ethanol and hydrogenated in the presence of 1.5 g. of platinum oxide catalyst for a period of 18 hours.

13 The reaction mixture was then filtered, the filtrate concentrated in vacuo and the resulting residue taken up into 200 ml. of aqueous acetic acid and 300 ml. of ether. This mixture was stirred for 1.5 hours, the acid layer was separated, basified with 20% aqueous sodium hydroxide solution to give an oily material which separated. This oil was extracted with methylene chloride, the methylene chloride extracts were washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the reaction mixture, 22.8 g. of an oil was left which gave with hydrogen chloride in ether a hydrochloride which was recrystallized from ethanolether to give 18.35 g. of cis- A a (p methoxyphenyl) 2 (benzylamino) cyclohexanemethanol hydrochloride of melting point 2105- 211 C. after one additional recrystallization from methanol-ether. A sample of this hydrochloride was treated with aqueous NaOH'to give cis-A-a-(p-methoxyphenyl)- 2-(benzylamino)cyclohexanemethanol as a free base having a melting point of 86-87 C. The analysis of the hydrochloride was as follows:

Analysis.Calcd. for C H NO -HCl: C, 69.69; H, 7.80; N, 3.87; Cl, 9.80. Found: C, 68.18; H, 7.86; N, 3.87; Cl, 9.80.

EXAMPLE 4 Cis-u-(3,4,5-trimethoxyphenyl)-2-(benzylamin0)cycl0- hexanemethanol and its hydrochloride A mixture of 83 g. (0.287 mole) of 2-(3,4,5-trimethoxybenzoyl)-cyclohexanone and 31 g. (0.29 mole) of benzylamine in 500 ml. of benzene was heated at reflux for a period of 1.5 hours. A total of 7.5 ml. of water was collected in a trap. The reaction mixture was thereupon concentrated in vacuo to give a residue which was dissolved in 500 ml. of ethanol and hydrogenated in the presence of 3.0 g. of platinum oxide catalyst for a period' of 20 hours at a hydrogen pressure of to 30 p.s.i. The reaction mixture was thereupon filtered to remove the catalyst and to the filtrate was added 3.0 g. of 10% palladium-on-carbon catalyst and the hydrogenation continued for another period of 24 hours at -30 p.s.i. The reaction mixture was filtered, concentrated in vacuo and the resulting residue taken up in 750 ml. of ether and 600 ml. of 10% aqueous hydrochloric acid. This mixture was stirred for 1 hour, after which an acid layer separated. The acid layer was filtered and basified with 20% aqueous sodium hydroxide solution, producing an oil which separated from the mixture. The oil was extracted into methylene chloride, washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried solution was evaporated, leaving a gum which gave with ethereal hydrogen chloride a white solid hydrochloride. This acid addition salt was recrystallized from methanol-ether to give 63 g. of impure cis-a-(3,'4,5- trimethoxyphenyl) 2 (benzylamino)cyclohexanemethanol hydrochloride of melting point 192-195 C. (previous sintering). After another recrystallization of a 20 g. sample from methanol-ether, the melting point was raised to 197-199" C. (previous sintering).

The latter material was treated with aqueous sodium hydroxide to give the free base which was extracted with methylene chloride and the extract was evaporated to give 13.75 g. of a gum-like material. An oxalate of this material was prepared and recrystallized from isopropanol to give 12.3 g. of melting point 208-209 C. The oxalate (12 g.) was treated with aqueous sodium hydroxide to give 9.92 g. of gummy material which partially solidified on standing and was crystallized from Skellysolve B hexanes to give 3.1 g. of cis-a-(3,4,5-trimethoxyphenyl) 2 (benzylamino)cyclohexanemethanol of melting point 113115 C. and a second crop of 1.33 g. of the same material. Recrystallization of this material gave pure cis-et-(3,4,5-trimethoxyphenyl)-2- (benzylamino)cyclohexanemethanol of melting point 114-115 C.

14 Analysis.Calcd. for C H NO C, 71.66; H, 8.11; N, 3.63. Found: C, 71.60; H, 8.19; N, 3.95.

Ultraviolet: A 235 (7,270); 258 (667); 267 (810); 279 (459).

EXAMPLE 5 Cis-a-(p-methoxyphenyl) -3-(3-hydroxyethylamin0) cyclohexanemethanol A solution of 23.0 g. (0.1 mole) of 2-(p-methoxybenzoyl)-cyclohexanone and 6.37 g. (0.105 mole) of 2- aminoethanol in ml. of benzene was heated at reflux for 2.25 hours during which 1.8 ml. of water was collected in a trap (Dean-Stark). The reaction mixture was thereupon concentrated in vacuo to give a yellow gum which was dissolved in 200 ml. of ethanol and hydrogenated in the presence of 1.5 g. of platinum oxide catalyst for a period of 20 hours. The catalyst was then removed by filtration, the filtrate concentrated in vacuo, the resulting residue dissolved in 200 ml. of 10% aqueous acetic acid-300 ml. of ether and stirred for a period of 30 minutes. The acid layer was then separated, basified with 20% sodium hydroxide solution and the mixture extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, saturated sodium chloride solotion and finally dried over anhydrous magnesium sulfate. After evaporation of the solution, there was left 25.61 g. of a white solid which was recrystallized from benzene-Skellysolve B hexanes several times to give cis-a-(p-methoxyphenyl)-2-(2-hydroxyethylamino)cyclohexanemethanol of melting point Ill-112 C. (solidifying the remelting at about 119-121 C.).

Analysis.-Calcd. for C H NO C, 68.78; H, 9.02; N, 5.01. Found: C, 68.47; H, 8.73; N, 5.24.

Ultraviolet: Amax. 226 (11,900); sl. sh 268 (1,200); 275 (1,600); 282 (1,300).

EXAMPLE 6 a-(3,4,5-trimeth0vcyphenyl) -2-(bulylamin0) cyclopentane methanol In the manner given in Example 5, 2-(3,4,5-trimethoxybenzoyl)cyclopentanone was refluxed with butylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give lit-(3,4,5- trimethoxyphenyl) 2 (butylamino)cyclopentanemethanol.

EXAMPLE 7 a-(3,4,5-trimeth0xyphenyl) -2-(hexylamlzno) cycloheptanemethanol In the manner given in Example 5, 2-(3,4,5-trimethoxybenzoyl)cycloheptanone was refluxed with hexylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(3,4,5- trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol.

EXAMPLE 8 u-(p-Methoxyphenyl)-2-(6-hydroxyhexylamin0) cyclopentanemethanol In the manner given in Example 5, Z-(p-methoxybenzoyl)cyclopentanone was refluxed with 6-aminohexanol in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(pmethoxyphenyl) -2 (6 hydroxyhexylamino)cyclopentame-methanol.

EXAMPLE 9 0L- (p-Ethoxyphenyl) -2-(ethylamino)cyclohexanemethanol In the manner given in Example 1, Z-(p-ethoxybenzoyl) cyclohexanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(pethoxyphenyl)-2-(ethylamino)cyclohexanemethanol.

EXAMPLE ot-(o-methoxyphenyl) -2-(3-meth0xypropylamino) cyclohexanemethanol In the manner given in Example 5, 2-(o-methoxybenzoyl)cyclohexanone was refluxed with B-methoxypropylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a- (o-rnethoxyphenyl) -2- (3 -methoxypropylamino cyclohexanemethanol.

EXAMPLE 11 a- (Z-methoxy-4-methylphenyl -2-anilin0qicl0hexane methanol u-(3,5-dimethyl-4-metho-xyphenyl -2- (propylamino) cyclohexanemethanol In the manner given in Example 1, 2-(3,5-dimethyl-4- methoxybenzoyl)cyclohexanone was refluxed with N-propylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(3,5-dimethylA-methoxyphenyl)2-(propylamino) cyciohexanemethanol EXAMPLE 13 ot- (p-Trifluoromethfl-phenyl) -2- (pen tylam ino) cyclohexanemeth anal In the manner given in Example 5, 2-(p-trifluorornethylbenzoyl)cyclohexanone was refluxed with pentylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(ptrifluoromethylphenyl) 2 (pentylamino)cyclohexanemethanol.

EXAMPLE 14 a-(p-Chlorophe'nyl) -2-(isopropylamino)cyclohexanemethanol In the manner given in Example 1, 2- (p-chlorobenzoyl) cyclohexanone was refluxed with N-isopropylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(pchlorophenyl) -2- iso pro pylamino) cyclohexanemethanol.

EXAMPLE 15 a-(o-Methylphenyl)-2-amin0cyclohexanemethdnol In the manner given in Example 1, 2-(o-methylbenzoyl) cyclohexanone was refluxed with benzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(omethylphenyl) -2-aminocyclohexanemethanol.

EXAMPLE 16 m-(p-Methylphenyl) -2-(ethylaminokyblohexana methanol In the manner given in Example 1, Z-(p-methylbenzoyl)cyc10hexanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(p-methylphenyl)-2-(ethylamino)cyclohexanemethanol.

EXAMPLE 17 u-(2,4-dimethylphenyl) -2-(p-toluidin0) cyclohexanemethanol In the manner given in Example 5, 2-(2,4-dimethylbenzoyl)cyclohexanone was refluxed with p-toluidine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give Ot-(2,4-dl methylphenyl) -2- (p-toluidino cyclohexanemethanol.

EXAMPLE 18 a- (2-m ethoxy-4-methylphenyl -2-(Z-ezhOxyethyIaminO) cyclohexanemethanol In the manner given in Example 5, 2-(2-rnethoxy-4- rnethylbenzoyl)cyclohexanone was refluxed with 2-eth0xyethylarnine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give u-(2-methoxy-4-methylphenyl) 2 (2 ethoxyethylamino) cyclohexanemethanol.

EXAMPLE 19 ocp-Ethoxypheny l -2- methy lamina) cyclooctanemethanol In the manner given in Example 1,2-(p-ethoxybenzoyl) cyclooctanone was refluxed with N-methyl-benzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give e-(pethoxyphenyl) -2- methylamino cyclooctanemethanol.

EXAMPLE 20 or-(2,3,4-trimethoxyphemyl) 2-(4-hydroxyhutylam ino) cyclooctememethariol In the manner given in Example 5, a-(2,3,4-trimethoxybenzoy1)cyclooctanone was refluxed with 4-hydroxybutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(2,3,4-trimethoxyphenyl)-2 (4 hydroxybutylamino) cyclooctanemethanol.

EXAMPLE 21 a- (p-Bromoph enyl -2- (isobuty lamrino) -cyclaocfan emethanol In the manner given in Example 5, 2-(p-bromobenzoyl)cyclooctanone was refluxed with isobutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(p-bro mophenyl -2- (isobutylamino) cyclooctanemethanol.

EXAMPLE 22 OL- (m-Methylphenyl) -2- (o-toluidin'o) cyclooctanemethanol In the manner given in Example 5, 2-(m-methylbenzoyl)cyclooctanone was refluxed with o-toluidine in benacne; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(m-methylphenyl) -2- (o-toluidino) cyclooctanemethanol.

EXAMPLE 23 ap-Fluorophenyl) -2-aminocyclohexan emethano l In the manner given in Example 1, Z-(p-fluorobenzoyl)cyclohexanone was refluxed with benzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(p-fluorophenyl -2-aminocyclohexanemethanol.

EXAMPLE 24 a-(2,5-dii0d0phenyl)-2-(methylamin0)cyclaheptanemethanol In the manner given in Example 1, 2-(2,5-diiodobenzoyl)-eycloheptanone was refluxed with N-methylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(2,5-diiodophenyl) -2- (methylamino cycloheptanemethanol.

EXAMPLE 25 a-(p-Bromophenyl) -2-(ethylamin0)cycl0pentanemethan0l In the manner given in Example 1, 2-(p-bromobenzoyl) cyclopentanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(pbromophenyl) -2- ethylamino cyclopentanemethanol.

EXAMPLE 26 a-(p-Hexylphenyl) -2-(4-eth0xybutylamin0)cyclopentanemethanol In the manner given in Example 5, Z-(p-hexylbenzoyl) cyclopentanone was refluxed with 4-ethoxybutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(p-hexylphenyl) -2- (4-ethoxybutylamino -cyclopentanemethanol.

EXAMPLE 27 a-(3,4-dipropylphenyl)-2-(S-hydroxypmpylamino) cycloheptanemethanol In the manner given in Example 5, 2-(3,4-dipropylbenzoyl)cycloheptanone was refluxed with 3-hydroxypropylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a (3,4-dipropylphenyl)-2-(3-hydroxypropy1amino)cycloheptanemethanol.

EXAMPLE 28 a-(2,4-diiodophenyl)-2-(ethylamin0) cycloheptanemethanol In the manner given in Example 1, 2-(2,4-diiodobenzoyl)cycloheptanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and in the presence of palladium-on-carbon catalyst to give u (2,4 diiodophenyl) 2 (ethylamino)cycloheptanemethanol.

As given in Examples 1 and other 1,3-amino alcohols of Formula III are obtained by reacting a 1,3-diketo compound I with a primary or secondary amine (V) and hydrogenating. Representatiave 1,3-amino alcohols thus obtained include:

a- (p-butoxyphenyl -2- (methylamino cyclopentanemethanol;

a- (p-isopropylphenyl) -2- (ethylamino cyclopentanemethanol;

a- (m-trifluoromethylphenyl) -2- (butylamino cyclopentanemethanol;

a- 2,4-diiodophenyl -2- 3-ethoxypropy1arnino cyclopentanemethanol;

a- (p-fluorophenyl -2- (m-toluidino) cyclopentanemethanol;

a- (p-isopropoxyphenyl -2-anilinocyclohexanemethanol;

u- (p-pentylphenyl -2-(hexylamino) cyclohexanemethanol;

cco-bromophenyl -2- S-hydroxypentylamino cyclohexanemethanol;

a- (2,3-diethylphenyl -2- Z-methoxyethylamino) cyclohexanemethanol;

a- (2,4-diethoxyphenyl) -2-aminocyclohexanemethanol;

a- 3,4,5 -triethoxyphenyl) -2- ethylamino cycloheptanemethanol;

02- 2-chl0rophenyl) -2- (o-toluidino) cycloheptanemethanol oc- 2,4-dichlorophenyl) -2- (4-ethoxybutylamino cyclohe ptanemethanol;

a- (p-trifluoromethylphenyl) -2- (propylamino cycloheptanemethanol a- (p-iodophenyl) -2- diethylamino cycloheptanemethanol;

a- (2,4-diethoxyphe-nyl) -2- (isobutylamino cyclooctanemethanol;

u- (o-fluorophenyl -2- (hexylamino cyclooctanemethanol;

oca-methoxyphenyl) -2-aminocyclooctanemethanol;

oc- (p-butoxyphenyl -2-anilinocyclooctanemethanol;

a- 3 ,5 -dipropylphenyl -2- (4-hydroxybutylamino cyclooctanemethanol,

and the like.

Cis A-a-(p-methoxyphenyl)-2-(N-methylbenzamido)cyclohexanemethanol and cis A-u-(p-methoxyphenyl) -2- (methylamino)cyclohexanemethanol benzoate ester A solution of 2.5 g. (0.010 mole) of cis-A-u-(p-methoxyphenyl -2- methylamino) cyclohexanemethanol and 2.5 g. (0.11 mole) of benzoic anhydride in 350 m1. of ether was allowed to stand at room temperature for 3 days. During this time, a solid separated from the solution. The mixture was taken up into additional ether and aqueous sodium bicarbonate solution. The ether layer was separated, washed with water and extracted with 5% aqueous hydrochloric acid. The ether layer was thereupon washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to give 1.97 g. of a gum which was crystallized from ether-Skelly solve B hexanes and thereupon from isopropanol to give cis A a (p-methoxyphenyl)-2-(N-methylbenzamido) cyclohexanemethanol of melting point 163-164 C.

Analysis.-Calcd. for C H NO C, 74.75 H, 7.70; N, 3.96. Found: C, 74.75; H, 7.79, N, 4.03.

The above extract obtained with 5% aqueous hydrochloric acid was basified with 10% sodium carbonate solution. The mixture was thereupon extracted with methylene chloride, the extract washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 1.78 g. of a gummy solid material. This material was triturated with pentane to give in two crops 1.4 g. of crude material which after recrystallization from isopropanol was pure cis-A-a-(pmethoxyphenyl) Z-(methylamino)cyclohexanemethanol benzoate ester of melting point 113-1 13.5 C.

Analysis.-Calcd. for C H NO C, 74.75 H, 7.70; N, 3.96. Found: C, 74.78; H, 7.79; N, 3.91.

EXAMPLE 30 EXAMPLE Cis-A-a- (gr-methoxyphenyl) -2-aminocyclohexanemethanol and its hydrochloride The hydrochloride was treated with aqueous sodium hydroxide and the mixture extracted with methylene chloride, the methylene chloride extracts were washed with aqueous sodium chloride and thereupon evaporated to give the free base, cis-A-a-(p-methoxyphenyl)-2-aminocyclohexane methanol of melting point 86-87 C.

Similarly, a suspension of 20 g. of the free base, cis-A- 0c (p methoxyphenyl) 2 (benzylamino)cyclohexanemethanol, in l l. of ethanol was hydrogenated "in the presence of 3 g. of 10% palladium-on-carbon catalyst for a period of 32 hours at a hydrogen pressure of 25-30 p.s.i. at room temperature. The reaction mixture was thereupon filtered and the filtrate was concentrated in vacuo to give a residue which was taken up in ether. The ether extract was evaporated and the resulting residue was recrystallized from Skellysole B hexanes several times to give cis-A-m- (p-methoxyphenyl)-Z-aminocyclohexanemethanol of melting point 86-88 C.

Analysis.--Calcd. for C H NO C, 71.45; H, 9.00; N, 5.95. Found: C, 71.10; H, 9.00; N, 5.88.

The preparation of cis-A-a-(p-methoxyphenyl)-2- aminocyclohexanemethanol can be carried out without the isolation of a benzylamino derivative in the following manner:

(2) Twenty-three grams of 2-(p-methoxybenzoyl) cyclohexanone was reacted with 11 g of benzylamine in 150 ml. of benzene, and subsequently reduced in the presence of platinum oxide catalyst in ethanol (150 ml). The mixture was thereupon filtered, and to the filtrate was added 2 g. of palladium-on-carbon catalyst, whereupon the mixture was hydrogenated for 24 hours at 35-50 p.s.i. Thereafter the mixture was again filtered, the filtrate evaporated in vacuo and the residue taken up with 200 ml. of 10% aqueous acetic acid and 250 ml. of ether. The acetic acid layer was separated and combined with a 50-ml. ester water extract of the ether layer. The combined acetic acid layer and water extract was basified with aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. This residue was recrystallized from ether-Skellysolve B hexanes to give 15.8 g. (67%) of cis-A-a-(p-methoxyphenyl)-2-aminocyclohexanemethanol of melting point 85-87 C.

EXAMPLE 31 CiS-B-oc- (p-methoxyphenyl -2-amin0cyclohexanemethanol and its oxalate Twenty ml. of triflnoroacetic acid was cooled to 05 C. and thereto was added 2.35 g. (0.01 mole) of cis-A-u- (p-methoxyphenyl)-2-aminocyclohexanemethanol in one portion. The ice bath used for cooling was removed and the greenish solution was stirred for 40 minutes. The reaction was thereupon cooled in an ice bath; 20 g. of ice, 50 ml. of water and 50 ml. of 20% aqueous sodium hydroxide solution were added and the mixture was stirred for 45 minutes. The mixture was then extracted with methylene chloride, the extract was washed with water, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried solution was evaporated to give 2.45 g. of a gummy material which according to vapor-phase chromatography contained six components ranging from 1.25% to 42.77%.

The gum-like material was reacted with oxalic acid in ether, the ether was evaporated and the salt was suspended in 200 ml. of methyl ethyl ketone. The methyl ethyl ketone suspension was warmed on the steam bath for about 5 minutes and filtered to give 1.5 g. of a white solid which was recrystallized from methanol-ether to give 1.424 g. (44%) of cis-B-a-(p-methoxyphenyl)-2- aminocyclohexanemethanol oxalate of melting point 17'8-179 C.

The oxalate (1.3 g.) was converted to the free base by dissolving the salt in methanol and adding excess sodium methoxide in methanol. The mixture was diluted with water and extracted several times with methylene chloride. The methylene chloride extract was washed with saturatde sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 1.03 g. of an oil which after trituration with pentane gave a solid. Recrystallization of this material from Skellysolve B hexanes gave 0.43 g. of cis-B-w(p-methoxyphenyl)-2-aminocyclohexanemethanol melting at 86-87 C.

Analysis.-Calcd. for C H NO C, 71.45; H, 9.00;

'N, 5.95. Found: C, 71.90; N, 8.93; N, 5.89.

Ultraviolet: A 225 (11,600); 274 (1,550); 281 1,300) 4 EXAMPLE 32 Cis-A -a-(p-meth0xypheny l) -2benzamidocycl0hexanemethanol To a solution of 2.4 g. (0.0102 mole) of ClS-A-OL- (p-methoxyphenyl)-2-aminocyc1ohexanemethanol in ml. of ether was added in one portion with shaking a solution of 2.3 g. (0.0102 mole) of benzoic anhydride in 50 ml. of ether. A white solid separated immediately; after 2 hours at room temperature, methylene chloride was added to dissolve the solid and the ether-methylene chloride solution was washed in succession with 10% aqueous hydrochloric acid, water, 5% aqueous sodium carbonate solution and water. The solution was thereupon dried over anhydrous magnesium sulfate and was concentrated in vacuo to give 2.55 g. (75%) of cisA-ap-methoxyphenyl -2-benzamidocyclohexanemethanol of melting point 1995-2005 C.

Analysis.Calcd. for C H NO C, 74.31; H, 7.42; N, 4.13. Found: C, 47.19; H, 7.83; N, 4.01.

Ultraviolet: A 225 (29,450); 267 sh (3,050); 274 sh (3,000); 280 sh (2,100).

EXAMPLE 33 Cis-A -a-(0-meth0xyphenyl) -2-amin0cycl0hexanemethanol A mixture of 23 g. (0.099 mole) of 2-(o-methoxybenzoyl)cyclohexanone and 11 g. (0.103 mole) of benzylamine in ml. of benzene was heated at reflux for 1.5 hours using a water trap (Dean-Stark). A total of 1.5 ml. of water was collected. The mixture was thereupon evaporated in vacuo, and the resulting residue was dissolved in 150 ml. of ethanol and hydrogenated in the presence of 1.5 g. of platinum oxide catalyst for a period of 24 hours at a presence of 20-50" p.s.i. During this time about 1.6 molar equivalents of hydrogen was absorbed. The reaction mixture was thereupon filtered to remove the catalyst, 1.5 g. of 10% palladium-on-carbon catalyst was added to the filtrate and the mixture was then hydrogenated for 24 hours at a hydrogen pressure between 40-50 p.s.i. The resulting reaction mixture was filtered and the filtrate was evaporated to give an oily material which was taken up with a mixture of 400 ml. of aqueous 10% acetic acid and 500 m1. of ether-methylene chloride (1:1). The acetic acid layer was separated, basified with 20% aqueous sodium hydroxide solution whereupon an oil separated which was extracted with methylene chloride. The methylene chloride extracts were washed with water, saturated aqueous sodium chloride solution and finally dried over anhydrous sodium sulfate. Evaporation of the solution resulted in a solid which was recrystallized from ether-Skellysolve B hexanes several times to give cis-A-a-(o-methoxyphenyl)-2-aminocyclohexanemethanol of melting point 122123 C.

Analysis.Calcd. for C H NO C, 71.45; H, 9.00; N, 5.95. Found: C, 71.59; H, 9.15; N, 6.31.

Ultraviolet: a 216 (8,450); 272 (2,150); 278 (2,000).

EXAMPLE 34 C iS-OL- 3 ,4,5 -trim etlzoxy phenyl -2-am inocyclohexanemethanol hydrochloride Three grams of cis oz (3,4,5-trimethoxyphenyl)-2- (benzylamino-cyclohexanemethanol in 150 ml. of ethanol was hydrogenated in the presence of 1 g. of 10% palladium-on-car-bon catalyst for a period of 6.5 hours at a pressure of 46-49 p.s.i. The reaction mixture was then filtered, the filtrate evaporated in vacuo, the residue dissolved in ether, filtered again, and the filtrate was admixed with an etheral solution of hydrogen chloride. The hydrochloride precipitated and was collected on a filter and recrystallized from methanol-ether to give 1.47 g. of cisor (3,4,5 trimethoxyphenyl)-2-aminocyclohexanemethanol hydrochloride of melting point 234 C.

Analysis.-Calcd. for C gH NO -HCl: C, 57.91; H, 7.90; N, 4.22; Cl, 10.69. Found: C, 58.11; H, 8.24; N, 4.24; Cl, 10.76.

Ultraviolet: A sh 232 (7,250); 268 (790); 278 (604).

EXAMPLE 35 a-(p-ethoxyphenyl) -2-aminocyclohexanemethanol In the manner given in Example 30 (Part 2), Z-(p-ethoxy-benzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give 11- (p-ethoxyphenyl -2-aminocyclohexanemethanol,

EXAMPLE 36 u-(3,4,5-trimetlzoxyphenyl) -2-amin0cycl0pentanemethanol In the manner given in Example 30 (Part 2), 2-(3,4,5- trimethoxybenzoyl)cyclopentanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(3,4,5-trimethoxyphenyl) 2 aminocyclopentanemethanol.

EXAMPLE 37 ot-(3,4,5-trimethoxyphenyl) -2-amin0cycl0heptanemethanol In the manner given in Example 30 (Part 2), 2-(3,4,5- trimethoxybenzoyl)cycloheptanone was treated with benylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-( 3,4,5 trirnethoxyphenyl) 2 aminocycloheptanemethanol.

EXAMPLE 38 a-(p-Methoxyphenyl) -2-amin0cycl0pentanemethanol In the manner given in Example 30 (Part 2), 2-(pmethoxybenzoyl)cyclopentane was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give no (p-methoxyphenyl -2-aminocyclopentanemethanol.

EXAMPLE 39 tx-(2-methoxy-4-methylphenyl)-2-amin0cycl0hexanemethanol In the manner given in Example 30 (Part 2), 2-(2- methoxy 4 methylbenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u: (2-methoXy-4-methylphenyl)-2-aminocyclohexanemethanol.

EXAMPLE 40 u-(3,5-dimethyl-4-meth0xyphenyl -2-amin0cycl0- hexanemethanol In the manner given in Example 30 (Part 2), 2-(3,5- dimethyl 4-methoxybenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(3,5-dimethyl-4-methoxyphenyl)-2-aminocyclohexanemethanol.

EXAMPLE 41 u-( p-Trifluoromethylphenyl )-2-amin0cycl0hexanemethanol In the manner given in Example 30 (Part 2), 2-(p-trifluoromethylbenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a (p trifluorornethylphenyl)-2-aminocyclohexanemethanol.

EXAMPLE 42 ap-Chlorophenyl) -2-amin0cycl0hexanonemethanol In the manner given in Example 30 (Part 2), 2-(pchlorobenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a (p chlorophenyl)-2-aminocyclohexanemethanol.

EXAMPLE 43 a-(p-Ethoxyphenyl)-2-aminocyclooctanemethanol In the manner given in Example 30 (Part 2), 2-(pethoxybenzoyl)cyclooctanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a- (p-ethoxyphenyl) -2-aminocyclooctanemethanol.

EXAM LE 44 a-(2,3,4-trimethoxyphenyl)-2-amin0cycl0octanemethanol In the manner given in Example 30 (Part 2), 2-(2,3,4- trimethoxybenzoyl)cyclooctanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(2,3,4-trimethoxyphenyl) 2 aminocyclooctanemethanol.

In the manner given in Example 30 (Part 2), condensing a diketo compound I with benzylamine and hydrogenating in the presence of platinum oxide catalyst, following .by hydrogenation with palladium-on-carbon catalyst, yields the corresponding a phenyI-Z-aminocycloalkanemethanols (IV, when R -R hydrogen). Representative ot-phenyl-2-aminocycloalkanemethanols thus obtained include:

cc- 2,4-dimethylphenyl -2-aminocyclohexanemethanol;

a- (p-bromophenyl -2-aminocyclohexanemethanol;

ap-iodophenyl -2-aminocyclohexanemethanol;

ap-fiuorophenyl -2-aminocyclohexanemethanol cz- 2,5 -diiodophenyl -2-aminocyclohexanemethanol;

a- (p-isopropoxyphenyl) -2-aminocyclohexanemethanol;

u- (p-pentylphenyl) -2-aminocyclohexanemethanol;

a- 2,4-diethoxyphenyl -2-aminocyclohexanemethanol;

u- (o-bromophenyl) -2-aminocyclohexanemethanol;

a- (p-hexylphenyl) -2-aminocyclopentanemethanol;

ap-butoxyphenyl -2-aminocyclopentanemethanol;

ap-iso pro pylphenyl) -2-a-minocyclopentanemethanol OL- (m-trifluoromethylphenyl) -2-aminocyclopentanemethanol;

u- 2,4-diiodophenyl) -2-aminocyc1opentanemethanol;

ap-fluo rophenyl) -2-amino cyclopentanemeth anol;

u- (p-bromophenyl) -2-aminocyclopentanemethanol;

u- 2,5-diiodophenyl -2-aminocycloheptanemethanol;

rx- 3,4-dipropylphenyl -2-aminocycloheptanemethanol;

a- 3 ,4,5-triethoxyphenyl -2-aminocycloheptanemethmethanol;

a- 2-chlorophenyl) -2-aminocycloheptanemethanol;

a- (2,4-dichlorophenyl -2-aminocycloheptanemethanol;

oc- (p-trifluoromethylphenyl -2-aminocycloheptanemethanol;

a- (p-iodophenyl) -2-aminocycloheptanemethanol;

am-methylphenyl -2-arninocyclooctanemethanol;

oc- (p-ethoxyphenyl) -2-aminocyclooctanemethanol;

a- (p-bromophenyl) -Z-aminocyclooctanemethanol;

a- (2,4-diethoxyphenyl) -2-aminocyclooctanemethanol;

ao-fiuorophenyl) -2-aminocyclooctanemethanol;

ap-methoxyp henyl -2-aminocyclooctanemethanol;

a- (p-methoxyphenyl -2-aminocyclooctanemethanol;

a- (p-butoxyphenyl -2-aminocyclooctanemethanol;

a- 3,5-dipropylphenyl -2-aminocyclooctanemethanol;

and the like;

23 EXAMPLE 45 Cis-A-nt-(methoxyphenyl )-2-acetamidocyclohexanemethanol In the manner given in Example 32, equimolar quantities of cis-A-E-(p-methoxyphenyl)-2-aminocyclohexanemethanol and acetic anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl -Z-acetamidocyclohexanemethanol.

EXAMPLE 46 Cis-A-a-(p-methoxyphenyl)-2-pr0pi0namid0cycl0- hexanemethanol In the manner given in Example 32, equimolar quantities of cis-A-a-(p-methoxyphenyl)-2-aminocyclohexanemethanol and propionic anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl)-2-propionamidocyclohexanemethanol.

EXAMPLE 47 Cis-A-u-(p-meth0xyphenyl) -2-butyramidocycl0- hexanemethanol In the manner given in Example 32, equimolar quantities of cis-A-a-(p-methoxyphenyl)-2-aminocyclohexanemethanol and butyric anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl)-2-butyramidocyclohexanemethanol.

EXAMPLE 48 Cis-A-a- (p-methoxyphenyl)-2-decan0amidocyclohexanemethanol In the manner given in Example 32, equimolar quantities of cis-A-w(p-methoxyphenyl)-2-aminocyclohexanemethanol and decanoic anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl )-2-decanoamidocyclohexanemethanol.

EXAMPLE 49 CiS-u- (3,4,5-trimeth0xyphenyl )-2-valeramid0cyclohexanemethanol In the manner given in Example 32, equimolar quantities of cis-a-(3,4,5-trirnethoxypheny1)-2-aminocyclohexanemethanol and valeric anhydride were reacted together at about 24-26 C. in ether to give cis-a-(3,4,S-trimethoxyphenyl) -2-valeramidocyclohexanemethanol.

EXAMPLE 50 u-(3,4,5-trimethoxyphenyl) -2-benzamid0cycl0- pentanemethanol In the manner given in Example 32, equimolar quantities of a-(3,4,5-trimethoxyphenyl)-2-arninocyc1opentanemethanol and benzoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,4,5-trimethoxyphenyl -2-benzamidocyclopentanemethanol.

EXAMPLE 51 a-(3,4,5-trimethoxyphenyl) -2-hexanoamid0cycl0- heptanemethanol In the manner given in Example 32, equimolar quantities of u-(3,4,5-trimethoxyphenyl)-2-arninocyc1oheptanemethanol and hexanoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,4,5-trimethoxyphenyl) -2-hexanoamidocycloheptanemethanol.

EXAMPLE 52 a- (p-Methoxyphenyl) -2-0ctan0amid0cycl0- pentanemethanol In the manner given in Example 32, equimolar quantities of a-(p-methoxyphenyl)-2-aminocyclopentanemethanol and octanoic anhydride were reacted together at about 24-26 C. in ether to give a-(p-methoxyphenyl)-2- octanoamidocyclopentanemethanol.

EXAMPLE 5 3 xp-Eth oxypheny l -2-n0n anoamidacycloh exanemeth anol In the manner given in Example 32, equimolar quantities of u-(p-ethoxyphenyl)-2-aminocyclohexanemethan0l and nonanoic anhydride were reacted together at about 2426 C. in ether to give a-(p-ethoxyphenyl)-2-nonanoamidocyclohexanemethanol.

EXAMPLE 54 00- p-Fluorophenyl) -2- (phenylacetamido) cyclehexanemethanol In the manner given in Example 32, equimolar quantities of u-(p-fluorophenyl)-Z-aminocyclohexanemethanol and phenylacetic anhydride were reacted together at about 24-26 C. in ether to give u-(p-fiuorophenyl)-2- (phenylacetamido)cyclohexanemethanol.

EXAMPLE 55 0c- (m-Trifluoromethylphenyl) -2-h eptanoamidocyclopentanemethanol In the manner given in Example 32, equimolar quantities of u-(m-trifluoromethylphenyl)-2-a.minocyclopentanemethanol and heptanoic anhydride were reacted together at about 2426 C. in ether to give a-(m-trifluoromethylphenyl -2-heptanoamidocyclopentanemethanol.

EXAMPLE 56 a-(2,4-dieth0xyphenyl)-2-(3-phenylpr0pion amido)cycl0- octanemethanol oc- (o-Fluorophenyl -2-bu'ty ramidocyclooctwnemethanol In the manner given in Example 32, equimolar quantities of u-(o-fluorophenyl)-2-aminocyclooctanemethanol and butyric anhydride were reacted together at about 24-26 C. in ether to give u-(o-fluorophenyl)-2-butyramidocyclooctanemethanol.

EXAMPLE 58 a-(3,5-dipr0pylphenyl) -2-benzamidocyclooctanemethanol In the manner given in Example 32, equimolar quantities of a-(3,5-dipropylphenyl)-2-aminocyclooctanemethanol and benzoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,5-dipropylphenyl)- 2-benza'midocyclooctanemethanol.

EXAMPLE 5 9 06- (p-Butoxyphenyl -2-decrm0am idocyclooctanemcthwnol In the manner given in Example 32, equimolar quantities of a-(p-butoxyphenyl)-2-aminocyclooctanemethanol and decanoic anhydride were reacted together at about 24-26 C. in ether to give ot-(p-butoxyphenyl)-2-decanoamidocyclooctanemethanol.

EXAMPLE 60 a- (p-Methoxyphenyl) -2-propionamidocyclooctanemethanol In the manner given in Example 32, equimolar quantities of a-(p-methoxyphenyl)-2-aminocyclooctanemethanol and propionic anhydride were reacted together at about 24-26 C. in ether to give a-(p-methoxyphenyD-2- propionamidocyclooctanemethanol.

EXAMPLE 61 u- (p-Methoxyphenyl)Z-(N-ethylbenzamido)cyclohexanemelhanol In the manner given in Example 29, approximately equimolar amounts of a-(p-methoxyphenyl)-2-(ethylamino)cyc1ohexanemethanol and benzoic anhydride were reacted in ether solution at about 2426 C. for three days to give ot-(p-rnethoxyphenyl)-2-(N-ethylbenzamido) cyclohexanemethanol.

EXAMPLE 62 a-(3,5-dimethyl-4-methoxyphenyl) -2-(N-pr0pylacetzrmido) cyclohexanemethanol In the manner given in Example 29, approximately equimolar amounts of a-(3,5-dimethyl-4-methoxyphenyl)- 2-(propylamino)cyclohexanemethanol and acetic anhydride were reacted in ether solution at about 2426 C. for three days to give e-(3,5-dimethyl-4-methoxyphenyl)- 2-(N-propylacetamido)cyclohexanemethanol.

EXAMPLE 63 ec-(p-Trifluoromethylphenyl)-2- (N-pentyldecanoamido) cyclohexanemethanol In the manner given in Example 29, approximately equimolar amounts of a-(p-trifiuoromethylphenyl)-2- (pentylamino)cyclohexanemethanol and decanoic anhydride were reacted in ether solution at about 2426 C. for three days to give a-(p-trifluoromethylphenyl)-2-(N- pentyldecanoamido cyclohexanemethanol.

EXAMPLE 64 et-(pChlorophenyl) -2-(N-isopropyloctanoamido)cyclohexanemethanol In the manner given in Example 29, approximately equimolar amounts of a-(p-chlorophenyl)-2-(isopropylamino)cyclohexanemethanol and octanoic anhydride were reacted in ether solution at about 2426 C. for three days to give u-(p-chlorophenyl)-2-(Nisopropyloctanoamido) cyclohexanemethanol.

EXAMPLE 65 ap-M ethy Iph enyl -2- (N -ethyl-3 pheny l propioruamido) cyclohexanem ethanol In the manner given in Example 29, approximately equimolar amounts of u-(p-methylphenyl)-2-(ethylamino)cyclohexanemethanol and 3-pheny1propionic anhydride were reacted in ether solution at about 2426 C. for three days to give a-(p-methylphenyl)-2-(N-ethyl-3- phenylpropionamido cyclohexanemethanol.

EXAMPLE 66 oc- (p-Ethoxyphenyl) -2-(N-methylacetamido) cyclooctanemethanol In the manner given in Example 29, approximately equimolar amounts of a-(p-ethoxyphenyl)-2-(methy1- amino)cyclooctanemethanol and acetic anhydride were reacted in ether solution at about 24-26 C. for three days to give a-(p-ethoxyphenyl)-2-(N-methylacetamido) cyclooctanemethanol.

EXAMPLE 67 a- (p-Bromophenyl) -2-(N-isobzttylhexanoamido) cyclooctanemethanol In the manner given in Example 29, approximately equimolar amounts of tx-(p-bromophenyl)-2-(isobutylamino)cyclooctanemethanol and hexanoic anhydride were reacted in ether solution at about 24-26 C. for three days to give u-(p-bromophenyl)-2-(N-isobutylhexanoamidot cyclooctanemethanol.

26 EXAMPLE 68 a-(2,5-'dii0d0phenyl)-2-(N-methylbenzamido) cycloheptanemethanol EXAMPLE 69 oc-( p-Bromophenyl -2- (N -ethylphenylacetamido) cyclopentanemethanol In the manner given in Example 29, approximately equimolar amounts of a (p-bromophenyl)-2-(ethylamino)cyclopentanemethanol and phenylacetic anhydride were reacted in ether solution at about 24-26 C. for three days to give a-(p-bromophenyl)-2-(N-ethylphenylacetamido)cyclopentanemethanol.

EXAMPLE 70 0t.- (p-Hexylphenyl)-2-[N-(4-ethoxybutyl) butyramido]- cyclopentanemethanol In the manner given in Example 29, approximately equimolar amounts of a-(p-hexylphenyl)-2-(4-ethoxybutylamino)cyclopentanemethanol and butyric anhydride were reacted in ether solution at about 24-26 C. for three days to give ot-(p-hexylphenyl)-2-[N-(4-ethoxybutyl butyramido] cyclopentanemethanol.

In the manner shown above, treating an a-(phenyl or substituted pheny1)-2-amino-(or N-monoalkyl or aryl substituted amino) cycloalkanemethanol with an acid anhydride of a hydrocarbon carboxylic acid, particularly alkanoic acids, containing from 2 to 12 carbon atoms, inclusive, and of benzoic and aralkanoic acids, e.g., benzoic, phenylacetic and 3-phenylpropionic acid, in ether solution at room temperature (IS-30 C.), yields the corresponding a-(phenyl or substituted phenyl)-2-(acylor substituted acylamido)cycloalkanemethanol. Representative compounds thus obtained include:

on (p-ethoxyphenyl -2-(N-ethylphenylacetamido) cyclohexanemethanol;

ec- (o-methoxyphenyl) -2-[N- 3-methoxypropyl) butyramido] cyclohexanemethanol;

OL-( 2-methoxy-4-methylphenyl -2- (N-phenylbenzamido) cyclohexanemeth anol;

oc- 3 ,5 -dimethyl-4-methoxyphenyl -2- (N-propylhexanoamido) cyclohexanemethanol;

ocp-trifluoromethylphenyl) -2- (N-pentylpropio namido cyclohexanemethanol;

a- (p-chlorophenyl) -2- (N-isopropylacetamido cyclohexanemethanol;

up-methoxyphenyl) -2- (N-ethylisobutyramido) cyclohex anemethanol;

a- 2,4-dimethylphenyl -2- (N-p-tolylvaleramido cyclohexanemeth anol;

oc- (p-bromophenyl) -2- N-ethylhexanoamido cyclopentanemethanol;

oc (p-hexylphenyl -2- [N-(4-ethoxybutyl benzamido] cycyopentanemethanol;

a- (p-butoxyphenyl) -2- (N-methylheptano amido) cyclopentanemethanol;

czp-isopropy-lphenyl -2- (N-ethyloctanoamido) cyclopentanemethanol;

u- (m-trifluoromethylphenyl) -2- N-butylnonano amido) cyclopentanemethanol;

a- 2,4-diiodophenyl -2- [N- 3 -ethoxypropyl decanoamido] cyclopentanemethanol;

O6- (p-fluorophenyl) -2- (N-m-tolylacetamido cyclopentanemethanol;

a- 3,4,5 -triethoxyphenyl) -2-acetamid0cycloheptanemethanol;

u- (2,4-diethoxyphenyl -2- 3-phenylpropionamido cycloheptanemethanol;

oc- (2,4-dichloropheny1) -2- [N- 4-ethoxybutyl butyramido] cycloheptanemethanol;

a- (p-trifiuoromethylphenyl -2-(N-propyldecanoamido cycloheptanemethanol;

oc- (2,5 -diidophenyl) -2- (N -methylnonanoamido) cycloheptanemethanol;

rx-(2-chlorophenyl -2- (N-o-tolylacetamido cycloheptanernethanol;

oz- (2,4-diethoxyphenyl) -2-(N-isobutylpropionamido) cycloheptanemethanol;

a-(o-fiuorophenyl) -2- (N-hexylbutyramido cyclooctanemethanol;

oc (p-methoxyphenyl -2- (phenylacetamido cyclooctanemethanol;

oc- (p-butoxyphenyl) -2- N-phenylbenzamido cyclooctanemethanol;

:x-( p-iodophenyl -2- 3-phenylpropionamido cyclohexanemethanol;

a- (p-fiuorophenyl -2- phenylacetamido cyclohexanemethanol;

04- 2,4-dimethylphenyl) -2-valeramidocyclohexan emethanol;

ocp-bromophenyl) -2-hexanoamidocyclohexanemethanol;

oc- (p-pentylphenyl -2-heptanoamidocyclohexanemethanol;

a- (o-bromophenyl) -2-o ctanoamidocyclohexanemethanol;

a- (p-hexylphenyl) -2-acetamidocyclopentanemethanol;

zxp-butoxypenyl) -2-propionamidocyclop entan emethau- (p-isopropylphenyl) -2-benzamidocyclopentanemetha- 04- m-trifluoro methylphenyl -2-isovaleramidocyclopentanemethanol;

a (p-bromophenyl) -2- phenylacetamido cyclopentanemethanol;

oc- 2,5 -diiodophenyl -2-benzamidocycloheptanemethanol;

u- 3,4-dipropylphenyl -2-butyramidocycloheptanemethanol;

u- (3 ,4, S-triethoxyphenyl) -2-isobutyramidocyclohept anemethanol a-(2-chlorophenyl -2-pr'opionamidocycloheptanemethaa-( 2,4-dichlorophenyl -2-valeramidocycloheptanemethaw (p-ethoxyphenyl) -2-acetamidocyclooctanemethanol;

a-(p-bromophenyl -2-octanoamidocyclooctanemethanol;

a- 2,4-diethoxyphenyl) -2-decano amidocyclooctanemethanol;

a-(o-iluorophenyl) -2-benzamidocyclooctanemethanol;

a-(p-methoxyphenyl) -2-( N-phenylpropionamido cyclooctanemethanol;

and the like.

EXAMPLE 71 Cis-2-( u,p-dimetk0xybenzyl) -N-methylcycl0hexylamine hydrogen oxalate and methanesulfonate A solution of 5 g. (0.02 mole) of cis-A-a-(p-methoxyphenyl) 2 (methylamino)cyclohexanemethanol in 400 ml. of methanol containing g. of hydrogen chloride was allowed to stand for 17 hours at room temperature. The reaction mixture was concentrated in vacuo below 45 C. to give a residue which was diluted with ice Water, basified with 20% aqueous sodium hydroxide, and then extracted with methylene chloride. The methylene chloride extracts were combined, washed With water, saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated to give 5 g. of an oil. The oil was chromatographed over 300 g. of neutral alumina. The column was eluted with l l. of 10% ether-90% Skellysolve B hexanes, 1 l. of 20% ether-80% Skellysolve B hexanes, 1 l. of 50% ether-50% Skellysolve 28 B hexanes, 2 l. of ether, 1 l. of 5% methanol95% ether, 1 l. of 10% methanol-% ether and 0.5 l. of methanol. The ether-Skellysolve B hexane fractions contained no product. The 2 l. of ether fractions were evaporated and gave 1.85 g. of oil. The fraction of 5% methanol-% ether contained 1.8 g. of oil and the fraction 10% methanol-90% ether contained 0.38 g. of oil. The 1.85 g. of oil obtained from the ether fractions was triturated with Skellysolve B hexanes to give a gummy solid, which was not further characterized. The mother liquors resulting from the trituration and the oil from the ether-methanol fractions were combined, concentrated in vacuo, the residue dissolved in ether, and an oxalate prepared and recrystallized from methanol-ether. The total of 3.68 g. (52%) of cis 2-(a,p-dimethoxybenzyl)-N-methylcyclohexylamine hydrogen oxalate was obtained, which after additional recrystallization from methanol ether had a melting point of 223224 C.

Ultraviolet: x 227 (12,350); 275 (1,500); 282 (1,350).

Analysis.-Calcd. fOI C16H25NO2'C2H2O4: C, H, 7.70; N, 3.96. Found: C, 61.49; H, 8.07; N, 4.06.

A sample of the oxalate was converted with aqueous sodium hydroxide to the free base, the free base was extracted with ether and treated with methanesulfonic acid to give the corresponding methanesulfonate of cis-2-(a,pdimehoxybenzyl) N-methylcyclohexylamine of melting poine l55 C.

Analysis.-Calcd. for C H NO -CH SO H: C, 56.81 H, 8.13; N, 3.90. Found: C, 56.47; H, 7.93; N, 3.98.

EXAMPLE 72 Cis-2-(a,p-dimethoxybenzyl) cyclohexylamine and maleate thereof A solution of 1.18 g. (0.005 mole) of cis-A-(p-me' thoxyphenyl)-2-aminocyclohexanemethanol in 100 ml. of methanol containing 2.5 g. of anhydrous hydrogen chloride was kept at room temperature for a period of 20 hours. The mixture was then concentrated in vacuo to give a residue which was diluted with ice water, basified with 20% aqueous sodium hydroxide and extracted with methylene chloride which was washed with water, saturated aqueous sodium chloride solution and concentrated finally to 1.48 g. of a yellow oil which gave a maleate in ether. The white salt was recrystallized from methyl ethyl ketone-ether to give 0.585 g. of cis-2-(a,p-dimethoxybenzyl)cyclohexylamine maleate which after additional recrystallization from methyl ethyl ketone-ether had a melting point of 142145 C.

Analysis.Calcd. for C H NO -C H O C, 62.45; H, 7.45; N, 3.83. Found: C, 62.50; H, 7.37; N, 3.82.

A sample of the maleate was treated with aqueous sodium hydroxide and the mixture was extracted with ether. The ether fractions were concentrated to give a residue which was several times recrystallized from pentane to give free cis-2-(a,p-dimethoxybenzyl)cyclohexylamine of melting point 5254 C.

EXAMPLE 73 2- a,3,4,5-retramethoxybenzyl) -N-methylcyclohexylamine and its hydrochloride A solution of 0.01 mole of a-(3,4,5-trimethoxyphenyl)-2-(methylamino)cyclohexanemethanol hydrochloride in ml. of water was basified by adding sufficient 10% aqueous sodium hydroxide solution. This solution was ex tracted three times with 100 ml. of methylene chloride. The methylene chloride solution was evaporated, leaving as an oily free base a-(3,4,5-trimethoxyphenyl)-2-(methylamino) cyclohexanemethanol.

A solution of the free base, ot-(3,4,5trimethoxyphenyl)-2-(methylamino)cyclohexanemethanol in 25 ml. of ether was added to 100 ml. of liquid ammonia containing 0.01 mole of sodium amide and the mixture was stirred for a period of 50 minutes, while cooling in Dry Iceacetone. A solution of 0.01 mole of methyl iodide in 5 ml. of ether was then added during minutes; the Dry Ice bath was removed and the mixture allowed to stir at room temperature for a period of 7 hours. It was then allowed to evaporate overnight (about 20 hours). To this reaction mixture was then added 50 ml. of water, and the mixture was extracted wtih three portions of 50 ml. each of methylene chloride. The combined methylene chloride extracts were washed with water, saturated salt solution, dried by passing through anhydrous sodium sulfate and evaporated, to give an oily product. The oil was dissolved in methylene chloride and chromatographed on 100 g. of Florisil (anhydrous magnesium silicate). The column of Florisil was eluted with four portions, each 200 ml., of a 3% acetone-97% Skellysolve B hexanes solution yielding an oil after evaporation of the solvents. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give 2-(a,3,4,5-tetramethoxybenzyl)-N-rnethylcyclohexylamine hydrochloride. A portion of this hydrochloride was treated with aqueous sodium hydroxide, the reaction mixture was extracted with methylene chloride, the extracts evaporated and the residues recrystallized from methanol to give 2-(a,3,4,5-tetramethoxybenzyl) -N-methylcyclohexylamine.

ExAMPLE 74 2-(m,3,4,5-tetramethoxybenzyl)-N-butylcyclopentylamine and hydrochloride thereof A solution of a-(3,4,5-trimethoxyphenyl)-2-(butylamino)cyclopentanemethanol (0.01 mole) in 50 ml. of methanol was treated with a solution of 5 g. of hydrogen chloride in 50 ml. of methanol and an additional 100 ml. of methanol was added. The solution was allowed to stand for 18 hours at about 25 C. and was then evaporated to dryness at 45 C. under reduced pressure to obtain Z-(a, 3,4,5 tetramethoxybenzyl)-N-butylcyclopentylamine hydrochloride as a residue. The residue was dissolved in 50 ml. of water; the solution was basified with aqueous sodium hydroxide solution and extracted with ether. The extract was washed with water, then with saturated sodium chloride solution, dried by passage through anhydrous sodium sulfate, and evaporated to dryness, to yield Z-(a, 3 ,4,5-tetramethoxybenzyl -N-butylcyclopentylamine.

EXAMPLE 75 2-(wethoxy-3,4,5-trimeth0xybenzyl)-N-hexylcycloheptylamine and its hydrochloride In the manner given in Example 74, u-(3,4,5-trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol in ethanol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2- a-ethoxy-3 ,4,5-trimelthoxybenzyl -N-hexfylcytzloheptylamine hydrochloride.

Treatment of this hydrochloride with an aqueous dilute sodium hydroxide solution yielded the free base, 2-(aethoxy 3,4,5 trimethoxybenzyl) N-hexylcycloheptylamine.

EXAMPLE 76 2-(a-propoxy-p-methoxybenzyl)-N-(6-hydroxyhexyl)- cyclopentylamine and its hydrochloride In the manner given in Example 74, a-(p-methoxyphenyl) 2-( 6-hydroxyhexylamino)cyclopentanemethanol in propanol solution containing hydrogen chloride was alowed to react for a period of 20 hours at room temperature to give 2-(a-propoxy-p-methoxybenzyl)-N-(6- hydroxyhexyl)cyclopentylamine hydrochloride.

Treatment of this hydrochloride with an aqueous dilute potassium hydroxide solution yielded the free base, 2- (u propoxy p methoxybenzyl)-N-(6-hydroxyhexyl) cyclopentylamine.

EXAMPLE 77 2-(a-butoxy-p-trifluoromethylbemzyl)-N-pentylcycl0- hexylomine and its hydrochloride In the manner given in Example 74, a-(p-trifluoro methylphenyl -2- (pentylamino cyclohexanemethanol in u-butanol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2-(a-butoxy-p-trifiuoromethylbenzyl)-N- pentylcyclohexylamine hydrochloride.

Treatment of this hydrochloride with an aqueous dilute sodium hydroxide solution yielded the free base, 2-(04- butoxy p trifiuoromethylbenzyl)-N-pentylcyclohexylamine.

EXAMPLE 78 2-(cap-diethoxybenzyl)-N-methylcycl00ctylatmine and its hydrochloride In the manner given is Example 74, a-(p-ethoxyphenyl)-2-(methylamino)cyclooctanemethanol in ethanol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2-(a,p-diethoxybenzyl)-N-methylcyclooctylamine hydrochloride.

Treatment of this hydrochloride with an aqueous dilute sodium hydroxide solution yielded the free base, 2-(m,pdiethoxybenzyl -N-methylcyclooctylamine.

EXAMPLE 79 2-(a-is0pr0p0xy-2,3,4-trimethoxybenzyl)-N-(4-hydr0xybutyl)cyclooctylamine and its hydrochloride In the manner given in Example 74, a-(2,3,4-trimethoxyphenyl) 2-(4-hydroxybutylamino)cyclooctanemethanol in isopropyl alcohol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2-(u-isopropoXy-2,3,4-trimethoxybenzyl) N (4-hydroxybutyl)cyclooctaylamine hydrochloride.

Treatment of this hydrochloride with an aqueous dilute sodium hydroxide solution yielded the free base, 2-(otisopropoxy 2,3,4 trimethoxybenzyl) N-(4-hydroxybutyl cyclooctylamine.

EXAMPLE 8O 2- a-hexyl0xy-2,5-diiodobenzyl) -N-methylcycloheptylamine and the hydrochloride thereof In the manner given in Example 73, a-(2,5-diiodophenyl)-2-(rnethylamino)cycloheptanemethanol in ether was added to a solution of sodium amide is liquid ammonia at about -70 C., and thereto was added an ether solution of hexyl iodide to give 2-(a-hexyloxy-2,5-diiodobenzyl)- N-methycycloheptylamine. Treatment .of the free base with etheral hydrogen chloride yielded the hydrochloride of 2- a-hexyloxy-2,S-diiodobenzyl -N-methylcyc1oheptylamine.

In the manner given in Example 74, other ethers of Formula IVa are prepared by reacting a lower alkanol, e.g., methanol, ethanol, propanol, 2-propanol, butanol or the like, with an alcohol of Formula IV or III in the presence of an acidic reagent, e.g., gaseous hydrogen chloride or hydrogen bromide. Representative ethers thus obtained include:

2- u,p-dimethoxybenzyl) -N- (N-hydroxyhexyl) cyclopentylamine;

2- tz-butoxy-p-bromobenzyl -N-ethylcyclopentylamine;

2- u-isobutoxy-p-hexylbenzyl -N- (4-ethoxybutyl) cyclopentylamine;

2- m-methoxy-p-butoxybenzyl) -N-methylcyclopentylamine;

2- u-ethoxy-p-isopropylbenzyl -N-ethylcyclopentylamine;

2-(u-ethoxy-m-trifluoromethylbenzyl)-N-buty1cyclopentylamine;

2-( u,4-dimethoxy-3,S-dimethylbenzyl)-N-propylcyc1ohexylamine;

2-(a-pentyloxy-p-chlorobenzyl)-N-isopropylcyclohexylamine;

2- u-propoxy-2,5-diiodobenzyl -N-methylcyclohexylamine;

2- a-ethoxy-p-pentylbenzyl -N-hexylcyclohexylamine;

2- ot-methoxy-2,3-diethylbenzyl -N- (Z-methoxyethyl) cyclohexylamine;

2- (a-propoxy-o-bromobenzyl) -N-(-hydroxypentyl) cyclohexyl amine;

2- ot-butoxy-2,4-diiodobenzyl -N-methylcycloheptylamine;

2- (a, 3 ,4,5-tetraethoxybenzyl cycloh eptylamine,

2- (u-propoxyo-chlorobenzyl -N- o-tolyl) cycloheptylamine;

2-(ot-methoxy-2,4-dichlorobenzyl) -N- (4-ethoxybutyl) cycloheptylamine;

2- a-ethoxy-p-trifluoromethylbenzy1) -N-propylcycloheptylamine;

2- (a-ethoxy-o-chl orobenzyl -N- (.o-tolyl cycloheptylamine;

2- a,2,4-triethoxybenzyl) -N-isobutylcyclooctylamine;

2- a-methoxy-o-fluo robenzyl) -N-hexylcyclooctylamine;

2- (a-ethoxy-3 S-dipropoxybenzyl -N- (4-hydroxybutyl) cyclooctylamine;

2- a-ethoxybenzyl -N-methylcyclooctylamine;

2- a-butoxy-p-bromobenzyl -N-isobutylcyclooctylamine;

2- a-hexyloxy-p-butoxyben zyl -N-phenylcyclooctylamine,

and the like.

In the manner given in Example 73, other ether compounds of Formula IVa can be obtained by reacting an alcohol of Formula IV, particularly one in which R is acyl with an alkyl halide in the presence of a strong base, at low temperature. Ethers thus obtained include:

2- a,p-dimethoxybenzyl -N-acetylcyclohexylamine 2- (u,p dimethoxybenzyl) -N-propio nylcyclohexylamine;

2- (u,p-dimethoxybenzyl -N-decanoylcyclohexylamine;

2- a,3 ,4,5-tetramethoxybenzyl -N-benzoylcyclopentylamine;

2- a-butoxy-3,4,S-trimethoxybenzyl -N-hexanoylcycloheptylamine;

2- nt-CthOXY-P-HlfithOXYbCflZYl -N-octanoylcyclopentylamine;

2- a-propoxy-p-ethoxybenzyl) -N-nonanoylcyclohexylamine;

2-( a-pentyloxy-p-fiuorobenzyl -N- (phenylacetyl cyclohexylamine;

2-( a-hexyloxy-m-trifluoromethylbenzyl) -N- heptan oylcyclopentylamine 2- a,2,4-triethoxybenzyl -N-( 3-phenylpropionyl) cyclooctylamine;

2- a-methoxy-o-fiuorobenzyl -N-buty rylcyclooctylamine;

2-(a,3,5-tripropoxybenzyl -N-benzoylcyclooctylamine;

2- u,p-dimethoxybenzyl -N-propionylcyclooctylamine;

2-( a-butoxy-3 5-dimethyl-4-methoxybenzyl -N-propy l- N-acetylcyclohexyl amine;

2-( u-isopropoxy p-tn'fluoromethylbenzyl) -N-pentyl-N- decanoylcyclohexylamine 2-( a-ethoxy-p-chlorobenzyl -N-isopropyl-N-propionylcyclohexyl amine;

2- (a-p ropoxy-p-methylbenzyl -N-ethyl-N- (3 phenylpropionyl) cyclophexylamine;

2- (a,p-diethoxybenzyl -N-methyl-N-acetylcyclooctylamine;

2-( a-methoxy-pbrornobenzyl) -N-methyl-N- benzoylcycl oheptyl amine;

2- ot-pentoxy-p-brom obenzyl -N-ethyl-N- (phenylacetyl) cyclopentylamine;

and the like.

EXAMPLE 81 2- a,p-dimeth0xy benzyl -N,N-dinrethylcyclohexylamine N-oxide To an ice-cooled solution of 7 mmoles of 2-(a,p-dimethoxybenzyl)-N,N-dimethylcyclohexylamine in 50 ml. of methanol was added 14 mmoles of m-chloroperbenzoic acid. The resulting colorless solution was allowed to stand in ice for 6 hours and then at room temperature (23 to 25 C.) for about 18 hours. It was evaporated to dryness at 35 C. to give an oily residue. To this residue was added 25 m1. of water followed by 25 ml. of 5% aqueous sodium hydroxide, and then the mixture was extracted three times with a total of ml. of methylene chloride. The methylene chloride extracts were combined, washed twice with saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give an oil. The oil was dissolved in 25 ml. of hot ethyl acetate and the cloudy solution was filtered through a sinter funnel. The resulting clear solution was evaporated to 8 ml. volume and cooled. The resulting crystals were recovered by filtration and washed with ether to give 2-(a,p-dimethoxybenzyl)N,N-dimethylcyclohexylamine N- oxide.

EXAMPLE 82 2- (a, p-dimethoxybenzyl -N ,N -dim.etl1y lcyclohexy lam inc methiodide A solution of 4 ml. of butyl lithium (0.01 mole) in hexane was added during 2 minutes to a solution of 0.01 mole of ot-(p-methoxyphenyD-Z(methylarnino)cyclohexanemethanol in 30 ml. of purified tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes and then cooled in a Dry Ice bath at 70 C. To this solution was added a solution of methyl iodide (1.42 g.; 0.01 mole) in 10 ml. of tetrahydrofuran, dropwise, over a period of 10 minutes. The mixture was stirred at 70 C. for a period of 1.5 hours and then at room temperature for 19 hours. To the solution was thereupon added water (50 ml.) and the solution was then extracted with three portions of 75 ml. each of methylene chloride. The organic extracts were combined, dried by passage through anhydrous sodium sulfate and evaporated to give crude product. The crude product was dissolved in 20 ml. methylene chloride and chromatographed over g. of neutral alumina. The material was first eluted with eight portions of 250 ml. of a 5% ether-95% Skellysolve B hexanes solution. After evaporation of the combined eluates, solid material was obtained. Further elution with two portions of 250 ml. of 25% ether-75% Skellysolve B hexanes, with two portions of 250 ml. each of 50% ether-50% Skellysolve B hexanes and with two portions of 250 ml. each of 75% ether-25% Skellysolve B hexanes gave solid material after evaporation of the combined eluates. The above fractions were all combined and re crystallized from ethanol to give 2-(a,p-dimethoxyben zyl)-N-methylcyclohexylamine.

Further elution of the column with 250 ml. of methanol gave material which was recrystallized from methanolether overnight in the refrigerator to give the methiodide of 2 -(a,p dimethoxybenzy1)- N,N dimethylcyclohexylamine.

EXAMPLE 83 Cis-B-Z-(u,p-dimethoxybenzyl)-N,N-dimethylcycl0hexylamine and its methanesmlfonate A mixture of 12.5 g. (0.05 mole) of ClS-B-2-(Ot,p-dlmethoxybenzyl)cyclohexylamine, 18 g. (0.39 mole) of formic acid (97100%) and 10 g. of 37% aqueous formaldehyde (0.123 mole) was heated on a steam bath for 19.5 hours. The reaction mixture was then coled, poured into water, and basified with 20% aqueous sodium hydroxide solution. The reaction mixture was extracted with ether, and the combined ether extracts were washed in succession with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The ether layer was dried and concentrated in vacuo to give a yellow oil. The yellow oil Was treated with methanesulfonic acid in ether to form cis-B-2-(a,p-dimethoxybenzyl)-N,N dimethylcyclohexylamine methanesulfonate which was recrystallized from methyl ethyl ketone, yielding 12.1 g. of melting point Ill-113 C. After re crystallization from isopropanol-ether, the salt had a melting point of 112-114 C. The salt was thereupon treated with aqueous sodium hydroxide solution, the mixture extracted with ether and the ether extract evaporated to give 6.83 g. (49.5%) of solid which after additional recrystallization from isopropanol-water at 2 C. gave cis-B-2-(a,p-dimethoxybenzyl)-N,N dimethylcyclohexylamine of melting point 5859 C.

Analysis.-Calcd. for C H NO C, 73.60; H, 9.81; N, 5.05. Found: C, 73.27; H, 9.97; N, 5.14.

Ultraviolet: A,,,,,,, 227 (12,350); sl. sh 268; 276 (1,450); 282 (1,250).

EXAMPLE 84 N- [2- (a,p-dimethoxybenzyl cy cloh exy l] benzamide A solution of 1.25 g. (0.005 mole) of cis-2-(a,p-dimethoxbenzyl)cyclohexylamine and 1.25 g. (0.0055 mole) of benzoic anhydride in 200 ml. of ether was left at room temperature for 2 hours. The reaction mixture was then washed in succession with 5% hydrochloric acid, Water, aqueous sodium carbonate solution, water and thereupon dried over anhydrous magnesium sulfate. The dried solution was evaporated to give a white solid which after recrystallization from Skellysolve B hexanes gave 1.25 g. (70.5%) of N- [2-(u,p-dimethoxybenzyl)cyclohexyl]benzamide of melting point 109-110 C.

Analysis.Calcd. for C H NO C, 74.75; H, 7.70; N, 3.96. Found: C, 75.05; H, 7.96; N, 4.00.

Ultraviolet: A 226 (23,250); sl. sh 266 (2,150; sl. sh 268 (2,150); 273 (2,050); 281 (1,450).

EXAMPLE 85 Cis-A-a-(p-methoxyphenyl)-2-(methylamin0)cycl0- hexanemethanol acetate ester A solution was prepared containing ml. of pyridine, 5 ml. of acetic anhydride, and 0.5 g. of CiS-A-ot-(P-IIIB- thoxyphenyl) -2- (methylamino cyclohexanemethanol. The mixture was allowed to stand at room temperature (24- 26 C.) for a period of 3 days. The mixture was thereupon treated with ether and aqueous sodium bicarbonate solution. The ether layer was separated, washed with water and extracted with 5% hydrochloric acid. The acid layer was separated from the ether layer, basified with 10% aqueous sodium carbonate solution and thereupon extracted with methylene chloride. The methylene chloride layers were washed with aqueous sodium chloride solution, water and thereupon dried over anhydrous sodium sulfate. The dried solution was concentrated to give a whitish solid which was several times recrystallized from isopropanol to give cis-A-a-(p-methoxyphenyl-2-(methylamino)cyclohexanemethanol acetate ester.

EXAMPLE 86 Cis-A-a-(p-methoxyphenyl) 2 (benzylamin0)cyclohexane-methanol butyrate ester In the manner given in Example 85, cis A a-(pmethoxyphenyD-Z (benzylamino) cyclohexanemethanol was treated in pyridine solution with butyric anhydride, the mixture after 3 days was extracted first with ether, then the ether solution with dilute hydrochloric acid, the hydrochloric acid extracts were separated, neutralized with dilute aqueous sodium carbonate solution, extracted with methylene chloride, the methylene chloride extracts evaporated and the resulting residue recrystallized to give cis-A a (p-methoxyphenyl) 2 (benzylamino) cyclohexamethanol butyrate ester.

EXAMPLE 87 Cis-a-(3,4,5-trimeth0xyphenyl) 2 (benzylamin0)cycl0- hexanemethanol decanoate ester A mixture of cis-u-(3,4,5-trimethoxyphenyl) 2 (benzylamino)cyclohexanemethanol and decanoyl chloride in pyridine was allowed to stand at room temperature (23-26 C.) for a period of 50 hours. The mixture was then poured into ice-water, and the aqueous mixture extracted with ether. The ether extracts were washed with EXAMPLE 88 a-(3,4,5-trimeth0xyphenyl)-2-(butylamin0)cycl0penlane-methanol laurate ester In the manner given in Example 87, a-(3,4,5-trimeth0xyphenyl)-2 (butylamino)cyclopentanemethanol was reacted with lauroyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(3,4,5-trimethoxyphenyl) 2 (butylamino)cyclopentanernethanol laurate ester.

EXAMPLE 89 a- (p-ethoxyphenyl -2-valeramidocycl00ctan emethanol heptarzemethanol phenylacetate ester In the manner given in Example 87, Ot'(3,4,5 trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol was reacted with phenylacetyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(3,4,5-trimethoxyphenyl) 2 (hexylamino)- cycloheptanemethanol phenylacetate ester.

EXAMPLE 90 ao-Methoxyphenyl) -2- (3-meth0xypropylamin0) cyclohexanemethanol 3-phenylpropi0nate ester In the manner given in Example 87, a-(o-methoxyphenyl) 2 .(3 methoxypropylamino)cyclohexanemethanol was reacted with 3 phenylpropionyl chloride in pyridine, the resulting reaction mixture Worked up as in Example 87 to yield u-(o-methoxyphenyl)-2-(3- methoxypropylamino)cyclohexanemethanol 3 phenylpropionate ester.

EXAMPLE 91 ec- (p-Trifluoromethylphenyl) -2- (pentylamino) cyclohexanemethanol propionate ester In the manner given in Example 87, a-(p-trifluoromethylphenyl) 2 (pentylamino)cyclohexanemethanol was reacted with propionic anhydride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield 1x-(p-trifluoromethylphenyl)-2-(pentylamino)cycylohexanemethanol propionate ester.

EXAMPLE 92 oz- (2,3,4-trimeth0xyphenyl) -2- (4-hydroxybutylamino cyclooctanemethanol diacetate ester In the manner given in Example 87, oc-(2,3,4-trirnethoxyphenyl) -2- 4-hydroxybutylamino cyclooctanemethanol was reacted with acetyl bromide in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(2,3,4-trimethoxyphenyl) 2 (4 hydroxybutylamino) cyclooctanemethanol diacetate ester.

EXAMPLE 93 u-(p-Bromophenyl -2- (isobutylamino) cyclooctanemethanol valerate ester In the manner given in Example 87, a-(p-bromophenyl)-2-(isobutylamino)cyclooctanemethanol was re acted with valeric anhydride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(p bromophenyl) 2 (isobutylamino)-cyc1ooctanemethanol valerate ester.

EXAMPLE 94 a- (2,5 -diiodophenyl -2-(methy lamina) eyeloheptanemethanol hexanoate ester In the manner given in Example 87, a-.(2,5-diiodophenyl) -2-(methylamino)cycloheptanemethanol was reacted with hexanoyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a- (2,5-diiodophenyl) 2 (methylamino) cycloheptanemethanol hexanoate ester.

EXAMPLE 95 a- (p-Bromophenyl) -2- (ethylamino)eyclopentanemethanol heptanoate ester In the manner given in Example 87, a-(p-brornophenyl)-2-(ethylarnino)cyclopentanemethanol was reacted with heptanoyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(p-bromophenyl)-2-(ethylamino) cyclopentanernethanol heptanoate ester.

EXAMPLE 96 Cis-a-(3,4,5-trimethoxyphenyl)-2-benzamidoeyclohexanemethanol benzoate ester A mixture of 5 mmoles of cis-a-(3,4,5-trimethoxyphenyl) -2-aminocyclohexanemethanol and 20 mmoles of benzoyl chloride in '8 ml. of pyridine was allowed to stand at room temperature(23-26 C.) for a period of 50 hours. The mixture was then poured into ice-water, and the aqueous mixture extracted with methylene chloride; the methylene chloride extracts were evaporated and the resulting residue was three times recrystallized from ethanol to give cis-a-(3,4,S-trimethoxyphenyl) 2 benzamidocyclohexanemethanol benzoate ester.

EXAMPLE 97 a-(3,4,5-trimethoxyphenyl)-2-ar:etamidocyelopentanemethanol acetate ester In the manner given in Example 96, a (3,4,5 trimethoxyphenyl) 2 aminocyclopentanemethanol was reacted with acetic anhydride in pyridine, the resulting reaction mixture worked up as in Example 96 to yield cc- (3,4,S trimethoxyphenyl) 2 acetamidocyclopentanemethanol acetate ester.

EXAMPLE 98 Cis-a-(3,4,5-trimethoxypkenyl) -2 (phenylaeetamido)- eyclohexanemethanol phenylaeetate ester A mixture of 20 mrnoles of cis-a(3,4,5-trimethoxyphenyl) 2 aminocyclohexanemethanol and phenylaeetyl chloride in 8 m1. of pyridine was allowed to stand at room temperature (23-26 C.) for a period of 50 hours. The mixture was then poured into ice-water and the aqueous mixture extracted with methylene chloride; the methylene chloride extracts were evaporated and the resulting residue was three times recrystallized from ethanol to give cis-a (3,4,5-trimethoxyphenyl) 2 (phenylacetamido)cyclohexanemethanol phenylacetate ester.

EXAMPLE 99 a-(3,4,5-trimethoxyphenyl)-2-(butyramid0) cycloheptanemethanal butyrate ester In the manner given in Example 96, a (3,4,5 trimethoxyphenyl)-2-aminocycloheptanemethanol was reacted with butyric anhydride in pyridine to yield a-(3,4,5- trimethoxyphenyl) 2 (butyramido)cycloheptanemethanol butyrate ester.

EXAMPLE 100 a-(p-Ethoxyphenyl) -2-valeramidocyclooctanemethanol valerate ester In the manner given in Example 96, a-(p-ethoxyphenyl)-2-arninocyclooctanemethanol was reacted with valeric anhydride in pyridine solution to give a-(p-ethoxyphenyn- 2-valeramidocyc1ooctanemethanol valerate ester.

EXAMPLE 101 41- (2,3,4-trimethoxyphenyl) 2 -deca'noamidocyclooctanemethanol decanoate ester EXAMPLE 102 u-(p-EthOxyphenyD-Z-(3-phenylpr0pionamid0)cyclooctanemethanol S-phenylpropionate ester In the manner given in Example 98, a-p-ethoxyphenyl)-2-aminocyclooctanemethanol was reacted with 3- phenylpropionyl chloride in pyridine solution to give a-(pethoxyphenyl) 2 (3-phenylpropionamido)cyclooctane methanol 3-phenylpropionate ester.

In the manner given in Example 87, other esters of Formula IVb, in which at least one of the parameters R or R is other than hydrogen, can be obtained by reacting a compound of Formula IV with an acylating reagent selected from the group of acid anhydrides and acid halides, particularly of alkanoic acids, cycloalkanoic and phenylsubstituted alkanoic acids containing up to and including 12 carbon atoms. Representative compounds thus obtained include:

nonanoates,

the acetates,

propionates, decanoates,

butyrates, undecanoates,

isobutyrates, dodecanoates,

valerates, benzoates,

isovalerates, phenylacetates,

hexanoates, aand B-phenylpropionates, heptanoates, 4-phenylbutyrates, octanoates,

aand fi-cyclopentylpropionates of a- (p-methoxyphenyl) 2- (ethylamino) cyclopentanemethanol;

a- (p-butoxyphenyl -2- (methylamino) cyclopentanemethanol;

[1- (p-isopropylphenyl -2- (ethylamino cyclopentanemethanol;

um-trifluoromethylphenyl) -2- (butylamino) cyclopentanemeth anol;

a- 2,4,-diiodophenyl) -2-( 3-ethoxypropylamino) cyclopentanemethanol;

ozp-fluorophenyl) -2- (m-toluidino) cyclopentanemethanol;

a- (p-isopropoxyphenyl) -2-anilinocyclohexanemethanol;

u- (p-pentylphenyl)-2-(hexylamino -cyclohexanemethanol;

oz- (o-bromophenyl -2- (S -hydroxypentylamino) -cyc1ohexanemethauol;

a- 2,3 -diethylphenyl) -2- Z-methoxyethylamino cyclohexanemethanol;

a-( 2,4-diethoxyphenyl) -2-aminocyclohexanemethanol;

a- 3 ,4,5-triethoxy=phenyl) -2- (ethylamino) cycloheptanemethanol;

04- Z-ciflorophenyl) -2- (o-toluidino) cycloheptanemethano a- (p-trifluoromethylphenyl -2- (propylamino cycloheptanemethanol;

cc- (p-iodophenyl) -2- (diethylamino cycloheptanemethanol;

a- 2,4-diethoxyphenyl) -2- (isobutyl amino) cyclooctanemethanol;

oc- (o-fiuorophenyl) -2- (hexyla-mino cyclooctanemethanol;

a- (p-methoxyphenyl) -2-aminocyclooctanemethanol;

a- (p-butoxyphenyl) -2-anilinocyclooctanemethanol;

a#( 3 ,5 -dipro pylphenyl) -2- (4hydroxybutylamino cyclooctanemethanol,

and the like.

In the manner given in Example 96, esters of Formula IVb in which one of the R or R groups is an acyl group,

can be obtained by reacting a compound of Formula IV in which R and R are both hydrogen with an acylating agent selected from the group consisting of acid halides and acid anhydrides in which the acid moiety is defined as above. Representative compounds thus obtained include:

oc- (p-hexylphenyl -2-propionamidocyclopentanemethanol propionate ester;

cz- (p-isopropylphenyl -2.-lauramidocyclopentanemethanol laurate ester;

a-(m-trifluoromethylphenyl)-2-benzamidocyclopentanemethanol benzoate ester;

a-(2,4-diiodophenyl)-2-(B-cyclopentylpropionamido)- cyclopentanemethanol p-cyclopentylpropionate ester;

a- (2,4-dimethylphenyl) -2-octanoamidocyclohexanemethanol octanoate ester;

up-fluorophenyl -2-decanoamidocyclohexanemethanol decanoate ester;

ap-b romophenyl) -2- 3-phenylpropionarnido cyclohexanemethanol B-phenylpropionate ester;

a-(p-pentylphenyl)-2-undecanoamidocyclohexanemethanol undecanoate ester;

11- (2,5 -diiodophenyl) -2- phenylacetamido cyclohexanemethanol phenylacetate ester;

a-(2,5-diiodophenyl)-2-butyramidocycloheptanemethanol butyrate ester;

a- 3 ,4,5-triethoxyphenyl) -2-hexano amidocycloheptanemethanol hexanoate ester;

ao-chlorophenyl -2-heptanoamidocycloheptanemethanol heptanoate ester;

a- (2,4-dichlorophenyl) -2- 4-phenylbutyramido cycloheptanemethanol 4-phenylbutyrate ester;

a-(p-trifluoromethylphenyl) -2-acetamidocycloheptanemethanol acetate ester;

am-methylphenyl) -2-benzamidocyclooctanemethanol benzoate ester;

a- (p-b romophenyl) -Z-lauramidocyclooctanemethanol laurate ester;

cw o-fiuorophenyl) -2-decano amidocyclooctanemethanol decanoate ester;

oc- 3,5 -dipropylphenyl) -2-nonanoamidocyclooctanemethanol nonanoate ester;

a- (p-butoxyphenyl) -2- (phenylacetamido) cyclooctanemethanol phenylacetate ester;

and the like.

EXAMPLE 103 Cis B 1 [2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine from cis-B-Z-(a,p-dimethxybenzyl) cyclohexylamine A mixture of 7.5 g. (0.03 mole) of cis-B-2-(a,p-dimethoxybenzyl)cyclohexylamine, g. of 1,5-diiodopentane and g. of anhydrous potassium carbonate in 100 ml. of dimethylformamide was stirred for 19 hours at room temperature. The reaction mixture was then stirred for 1 hours at 90-100 C., and then under continuous stirring allowed to cool to room temperature. The mixture was thereupon diluted with 500 ml. of ether, the solids were removed by filtration and the filtrate concentrated in vacuo at about 10 mm. Hg. After cooling, the residue solidified. The solid material was diluted with water, filtered, the residue on the filter washed with water and recrystallized several times from ethanol to give a total of 7.8 g. (82%) of cis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine of melting point 8284 C. This product is a useful diuretic.

EXAMPLE 104 Cis-A-a-(p-methoxyphenyl) -2-piperidin0cycl0- hexanemethanol A mixture of 1.10 g. of cis-A-ix-(p-methoxyphenyl)-2- aminocyclohexanemethanol, 1.6 g. of 1,5-diiodopentane and 7 g. of anhydrous potassium carbonate in 75 ml. of methyl ethyl ketone was stirred at reflux for 16.5 hours. The mixture was concentrated in vacuo, the residue was taken up into methylene chloride-water and the organic layer was separated, washed with water, saturated sodium chloride solution and finally dried over anhydrous magnesium sulfate. The dried solution was thereupon evaporated to give an oily material which was chromatographed on a column containing g. of silica. The column was eluted with five portions of 100 ml. each of methylene chloride, then with ten portions of methylene chloride containing 2.5% methanol (each portion 100 ml), then with ten 100-ml. portions containing 5% methanol, and then with ten portions containing 10% methanol. Fractions containing 2.5 and 5% methanol were combined, evaporated and the solid residue was three times recrystallized from pentane to give cis-A-ix- (p methoxyphenyl)-2-piperidinocyclohexanemethanol of melting point 81.5-83.5 C. in 37% yield. The hydrochloride prepared in ether with gaseous hydrogen chloride and purified by recrystallization from isopropanolether melted at 217.5-221 C. Cis A a (p-methoxyphenyl)-2-piperidinocyclohexanemethanol is a useful diuretic compound.

In the same manner, cis-A-ot-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol can be prepared from cis- A a (p-methoxyphenyl)-2-aminocyclohexanemethanol with 1,5-dibromopentane.

EXAMPLE C is-B-a-(p-methoxy phenyl )-2-piperidinocycl0- hexanemethanol In the manner given in Example 104, 1.1 g. of cis-B- a (p-methoxyphenyl)-2-aminocyclohexanemethanol, 1.6 g. of 1,5-diiodopentane and 7 g. of anhydrous potassium carbonate in 75 ml. of methyl ethyl ketone was stirred for a period of 23 hours to give a total of 363 mg. (26 of cis-B-a-(p-methoxyphenyl) -2-piperidinocyclohexanemethanol of melting point 136-138 C. having diuretic activity.

EXAMPLE 106 Cis-B-a-(3,4,5-trimethoxyphenyl)-2-piperidinocycl0- hexanemethanol In the manner given in Example 104, cis-B-ot-(3,4,5-trimethoxyphenyl)-2-aminocyclohexanemethanol was reacted with 1,5-cliiodopentane in the presence of potassium carbonate to give cis B a (3,4,5-trimethoxyphenyl)-2- piperidinocyclohexanemethanol, a diuretic.

ExAMPLE 107 a-(p-Fluorophenyl) -2-piperidin0cyclopentanemethanol In the manner given in Example 104, a-(p-fluorophenyl)-2-aminocyclopentanemethanol was treated with 1,5-dii0dopentane in the presence of potassium carbonate to give diuretically active a-(p-fiuorophenyl)-2-piperidinocyclopentanemethanol.

EXAMPLE 108 a- (2,4-dimethylphenyl)-2-piperidin0cyclohexanemethanol In the manner given in Example 104, a-(ZA-dimethylphenyl)-2-aminocyclohexanemethanol was treated with 1,5-diiodopentane in the presence of potassium carbonate to give diuretically active on (2,4 dimethylphenyl) 2- piperidinocyclohexanemethanol.

EXAMPLE 109 a- (2,5-dii0a'0phenyl) -2-piperidin0cycloheptanemethanol In the manner given in Example 104, 0L-(2,5-dll0d0- phenyl)-2-aminocycloheptanemethanol was treated with 1,5-dibromopentane in the presence of potassium carbonate to give diuretically active a-(2,5-diiodophenyl)-2- piperidinocycloheptanemethanol.

EXAMPLE 1'10 .a- (p -Butoxyphenyl)-2-piperidinocyclooctanemethanol In the manner given in Example 104, a-(p-butoxyphenyl)-2-aminocyclooctanemethanol was reacted with 1,5-diiodopentane in the presence of potassium carbonate to give diuretically active ot-(p-butoxyphenyl)-2-piperidinocyclooctanemethanol.

In the same manner given in Example 104, other 2- piperidinocycloalkanemethanols can be made by reacting a selected 2-aminocycloalkanemethanol with 1,5-diiodoor 1,5-dibromopentane in the presence of a. strong base such as potassium carbonate, sodium carbonate or the like. Similarly, ethers and esters of such Z-aminocycloalkanemethanols can be converted to the corresponding 2-piperidinocycloalkanemethanol esters or ethers. Representative compounds thus obtained which have diuretic activity include:

ap-bromophenyl) -2-piperidinocyclohexanem ethanol;

ato-methoxyphenyl -2-piperidinocyclohexanemethanol;

a- (2,5 -diiodopl1enyl) -2-piperidinocyclohexanemethanol;

ot- (p-hexylphenyl) -2-piperidinocyclopentanemethanol;

otp-isopropylphenyl) -2-piperidinocyclopentanemethanol;

u- (m-trifluoromethylphenyl) -2-pinperidinocyclopentanemethanol;

u-( 2,4-diiodophenyl -2-piperidinocyclopentanemethanol;

a- 3,4-dipropylphenyl) -2-piperidinocyclopentanemethanol;

a- 2,4-dichlorophenyl -2-piperidinocycloheptanemethanol;

oz-( p-trifluoromethylphenyl) -2-piperidinocycloheptanemethanol;

ap-iodophenyl) -2-piperidin ocycloheptanemethanol;

a- (p-ethoxyphenyl -2-piperidinocyclooctanemethanol;

a- (p-bromophenyl) -2-piperidinocyclooctaneme'th anol;

a- (2,4-diethoxyphenyl -2-piperidino cyclooctanemethanol;

cc- 3,5-dipropylphenyl) -2-piperidinocyclooctanemethanol;

and in particular the methyl, ethyl propyl, and butyl ethers thereof, and the like.

EXAMPLE 1 l 1 a- (p-Methoxypiizenyl) -2- (dimelhylamino)cyclohexanemethanol A solution of 0.01 mole of u-(p-l'l'1thOXYph6Xlyl)-2 (methylamino)cyclohexanemethanol, 0.01 mole of methyl iodide and 0.01 mole of potassium carbonate in 60 ml. of methanol was heated for 24 hours to reflux. The mixture was cooled, filtered, the filtrate dried over anhydrous sodium sulfate and evaporated to leave a solid residue. The residue was extracted with methylene chloride, the methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue. Recrystallization of the residue from ethanol gave a p methoxyphenyl) Z-(dimethylamino)cyclohexanemethanol.

EXAMPLE 112 a-(3,4,5-trimetlzoxyphenyl) -2-(N-ethylbnzYlamino)- cyclohexanemethauol In the manner given in Example 111, treating tit-(3,4,5- trimethoxyphenyl -2- benzylamino) cyclohexanemethanol with ethyl iodide and potassium carbonate in methanol produces a (3,4,S-trimethyoxyphenyl)-2-(N-ethylbenzylamino) cyclohexanemethanol.

EXAMPLE 113 ap-F l uorophenyl -2- (N -prpyl-p-t0luidi n0) cyclopentanemethanol In the manner given in Example 111, treating a-(pfluorophenyl) -2- p-toluidino cyclopentanem ethanol with propyl iodide and potassium carbonate in methanol pro- 40 duces a (p-fiuorophenyl)-2- (N-propyl-p-toluidino) cyclopentanemethanol EXAMPLE 1 14 ct- (3 ,4,5 -trieth0xy phenyl -2- (diethylamino cycloheptanem ethanol In the manner given in Example 111, treating lit-(3,4,5- triethoxyphenyl) 2 (ethylamino)cycloheptanemethanol with ethyl iodide and potassium carbonate in methanol produces u-(3,4,5-triethoxyphenyl) 2 (diethylamino) cycloheptanemethanol.

EXAMPLE a-(o-Fluorophenyl) -2-(N-butylhexylamin0)cyclooctwnemethanol In the manner given in Example 111, treating ot-(ofluorophenyl -2- (hexylamino cyclooctanemethanol with butyl iodide and potassium carbonate in methanol produces a-(o-fluorophenyl) 2 (N-butylhexylamino)cyclooctanemethanol.

EXAMPLE 1 16 Cis-2-(a,p-dimetho,xybenzyl)-N-methyl-N-butylcyclohexylamine In the manner given in Example 111, heating 0.01 mole of cis-Z-(u,p-dimethoxybenzyl)-N-methylcyclohexylamine With 0.01 mole of butyl iodide in ethanol in the presence of 0.01 mole of potassium carbonate yields cis-2-(a,pdimethoxybenzyl)-N-methyl-N-butylcyclohexylamine.

EXAMPLE 1'17 a-(p-Methoxyphenyl)-2-(N-me'thylbenzylamino)cyclohexanemerhanol benzoate ester In the manner given in Example 111, heating in waterfree methanol solution 0.01 mole of u-(p-methoxyphenyl)-2-(methylamino)cyclohexanemethanol benzoate ester, 0.01 mole of benzyl chloride and 0.01 mole of potassium carbonate yields a-(p-methoxyphenyD-Z-(N- methylbenzylamino)cyclohexanemethanol benzoate ester.

In the manner given in Example 111, other monoalkylaminocycloalkane compounds of Formulae III, IV, IVa or IVb can be converted to the corresponding tertiary amino compounds. Representative compounds thus obtained include:

a- 3 ,4,5-trimethoxyph enyl) -2- (N-methyloctylamino) cyclohexanemethanol;

a- 3 ,S-dimethyl-4-methoxyphenyl -2- (N-propylpentylamino cyclohexanemethanol;

OC- (p-brornophenyl -2- (N-decylisobutylamino cyclooctanemethanol;

ap-trifluoromethylphenyl -2- (N-methylpen'tylamino) cyclohexancmethanol;

ot- (p-ethoxyphenyl -2- diethylamino cyclohexanemethanol;

a- (3 ,4,5-trimethoxyphenyl -2- (N-ethylbutylamino) cyclopentanemethanol oc- (3,4, S-triniethoxyiahenyl)-2-(N-dodecylhexylamino) cycloheptanemethanol;

Ot- (p-bromophenyl) -2- (diethylamino cyclopentanemethanol;

2- ot,3,4,5-tetramethoxybenzyl -N,N-dimethylcyclohexylamine;

2- a,3 ,4,5-tetramethoxybenzyl) -N-butyl-N-hexylcyclopentylamine;

2-( u-ethoxy-3 ,4,5 -trimethoxybenzyl) -N-ethyl-N-hexylcycloheptylamine;

2- (a,p -diethoxybenzyl) -N-methyl-N-ethylcyclooctylamine;

2- aethoxy-m-trifluoromethylbenzyl) -N-butyl-N-benzylcyclopentylamine;

a- (3 ,4,5-trimethoxyphenyl) -2- (N-butylbenzylamino) cyclopentanemethanol laurate ester;

a- (3 ,4,5-trimethoxyphenyl) -2- (N-ethylhexylamino) cycloheptanemethanol phenylacetate e ster; 

